Tatsuya Tominaga, Hideharu Abe, Akira Mima, Kojiro Nagai, Matsubara Takeshi and Toshio Doi : Role of Smad 1 Signaling in Pathogenesis of Diabetic Nephropathy, Nova Science Publishers, Sep. 2012.
Masanori Minato, Taichi Murakami, Naoki Takahashi, Hiroyuki Ono, Kenji Nishimura, Masanori Tamaki, Kojiro Nagai, Hideharu Abe, Masayuki Iwano, Kensuke Joh and Toshio Doi : Glucocorticoid-dependent Tubulointerstitial Nephritis with IgM-positive Plasma Cells Presenting with Intracellular Crystalline Inclusions within the Rough Endoplasmic Reticulum., Internal Medicine, 2021.
(要約)
Tubulointerstitial nephritis (TIN) with IgM-positive plasma cells (IgMPC-TIN) is an autoimmune kidney disease characterized by IgM/CD138-double-positive plasma cell infiltration in the tubulointerstitium. A 50-year-old man developed IgMPC-TIN and presented with crystalline inclusions in the rough endoplasmic reticulum. Intracellular crystal formation is a rare finding in paraprotein-related kidney diseases, but this case showed no pathogenic monoclonal immunoglobulin. Prednisolone (PSL, 30 mg) improved the TIN, but PSL tapering resulted in the recurrence of TIN. Combination therapy with 15 mg PSL and 150 mg mizoribine ultimately stabilized TIN. This case offers original evidence concerning the pathophysiology and treatment strategy of IgMPC-TIN.
Taichi Murakami, Kenji Nishimura, Hiroyuki Ono, Sayo Ueta, Eriko Shibata, Seiji Kishi, Masanori Tamaki, Keiko Miya, Hisato Shima, Manabu Tashiro, Tomoko Inoue, Kazuhiko Kawahara, Kojiro Nagai, Hideharu Abe, Jun Minakuchi and Toshio Doi : Clinical characteristics associated with 1-year tolvaptan efficacy in autosomal dominant polycystic kidney disease with a wide range of kidney functions., The Journal of Medical Investigation : JMI, Vol.67, No.3.4, 315-320, 2020.
(要約)
Autosomal dominant polycystic kidney disease (ADPKD) develops into end-stage kidney disease by 65 years of age in an estimated 45%-70% of patients. Recent trials revealed that tolvaptan inhibits disease progression both in early-stage or late-stage ADPKD ; however, stratified analysis showed a difference of favorable factors correlated with tolvaptan efficacy between early-stage and late-stage ADPKD. Thus, we examined the efficacy of tolvaptan in ADPKD with a wide range of estimated glomerular filtration rates (eGFR). We enrolled 24 patients with eGFR 35.3 (28.0-65.5) ml / min / 1.73m2 and evaluated treatment effect as ΔΔeGFR (ml / min / 1.73m2 / year) or ΔΔtotal kidney volume (TKV) (% / year) that was calculated as post-treatment annual change - pre-treatment annual change. Pre ΔeGFR was significantly low in eGFR responders, defined as ΔΔeGFR > 0 ml / min / 1.73m2 / year. In eGFR responders, pre ΔeGFR, post ΔeGFR, eGFR, TKV, and proteinuria were significantly correlated with ΔΔeGFR. In TKV responders defined as ΔΔTKV > 5 % / year, we identified hypertension history, proteinuria, TKV, and post ΔTKV as significantly correlated factors with ΔΔTKV. In conclusion, pre ΔeGFR may be a predictive factor of therapeutic efficacy on kidney function. Tolvaptan may have greater efficacy in early-stage ADPKD with rapid GFR decline or with well-controlled blood pressure. J. Med. Invest. 67 : 315-320, August, 2020.
Kenji Nishimura, Taichi Murakami, Toshihiro Sakurai, Masashi Miyoshi, Kiyoe Kurahashi, Seiji Kishi, Masanori Tamaki, Tatsuya Tominaga, Sumiko Yoshida, Kojiro Nagai, Hideharu Abe, Shu-Ping Hui, Kazuhiko Kotani and Toshio Doi : Circulating Apolipoprotein L1 is associated with insulin resistance-induced abnormal lipid metabolism., Scientific Reports, Vol.9, No.1, 14869, 2019.
(要約)
Circulating ApolipoproteinL1 (ApoL1) is a component of pre-β-high-density lipoprotein (HDL), however little is known about the relationship of ApoL1 with cardiometabolic factors. Considering previous studies reporting the correlation of ApoL1 to triglyceride, we have hypothesized that ApoL1 associates with insulin-related metabolism. The current study examined their associations in 126 non-diabetic subjects and 36 patients with type 2 diabetes (T2DM). Non-diabetic subjects demonstrated triglyceride (standardized coefficients [s.c.] = 0.204, p < 0.05), body mass index (s.c. =0.232, p < 0.05) and HDL cholesterol (s.c. = -0.203, p < 0.05) as independent determinant of ApoL1 levels, and the significant elevation of ApoL1 in metabolic syndrome. Lipoprotein fractionation analysis revealed the predominant distribution of ApoL1 in large HDL fraction, and the significant increase of ApoL1 in large LDL fraction in high ApoL1 samples with insulin resistance. In T2DM, ApoL1 was higher in T2DM with metabolic syndrome, however ApoL1 was lower with β cell dysfunction. Insulin significantly promotes ApoL1 synthesis and secretion in HepG2 cells. In conclusion, circulating ApoL1 may be associated with abnormal HDL metabolism in insulin resistant status. This may suggest a regulation of insulin signal on the ApoL1 level, leading to offer a novel insight to the ApoL1 biology.
Masashi Miyoshi, Yusuke Inoue, Mai Nishioka, Akishige Ikegame, Takayuki Nakao, Seiji Kishi, Toshio Doi and Kojiro Nagai : Clinical evaluation of presepsin considering renal function., PLoS ONE, Vol.14, No.9, e0215791, 2019.
(要約)
Presepsin, a glycoprotein produced during bacterial phagocytosis, is used as a sepsis marker for bacterial infections. However, presepsin levels are affected by renal function, and the evaluation criteria according to kidney function or in chronic kidney diseases remain controversial. Furthermore, presepsin may be increased by sample stirring, but no studies have evaluated this effect.In this study, we excluded the effect of stirring by standardizing the blood collection conditions, analyzed the influence of kidney function on presepsin concentrations, and recalculated the reference range based on the findings. EDTA-whole blood from 47 healthy subjects and 85 patients with chronic kidney disease was collected to measure presepsin by PATHFAST. Presepsin was found to be significantly correlated with the levels of creatinine (r = 0.834), eGFRcreat (r = 0.837), cystatin-C (r = 0.845), and eGFRcys (r = 0.879). Furthermore, in patients with CKD, presepsin levels stratified by eGFRcys showed a significant increase in the CKD G2 patient group and with advancing glomerular filtration rate stage. The following values were obtained: Normal: 97.6 ± 27.4 pg/mL, CKD G1: 100.2 ± 27.6 pg/mL, CKD G2: 129.7 ± 40.7 pg/mL, CKD G3: 208.1 ± 70.2 pg/mL, CKD G4: 320.2 ± 170.1 pg/mL, CKD G5: 712.8 ± 336.3 pg/mL. The reference range, calculated by a nonparametric method using 67 cases of healthy volunteers and patients with chronic kidney disease G1, was found to be 59-153 pg/mL, which was notably lower than the standard reference range currently used. Presepsin concentrations were positively correlated with a few biomarkers of renal function, indicating the necessity to consider the effect of renal function in patients with renal impairment. Using the recalculated reference range considering kidney function may improve the accuracy of evaluating presepsin for diagnosis of sepsis compared to the standard reference currently in use.
Akiko Sakurai, Hiroyuki Ono, Arisa Ochi, Motokazu Matsuura, Sakiya Yoshimoto, Seiji Kishi, Taichi Murakami, Tatsuya Tominaga, Kojiro Nagai, Hideharu Abe and Toshio Doi : Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy., PLoS ONE, Vol.14, No.5, 2019.
(要約)
Diabetic nephropathy (DN) is among the most serious complications of diabetes mellitus, and often leads to end-stage renal disease ultimately requiring dialysis or renal transplantation. The loss of podocytes has been reported to have a role in the onset and progression of DN. Here, we addressed the activation mechanism of Smad3 signaling in podocytes. Expression of RII and activation of Smad3 were induced by AGE exposure (P<0.05). Reduction of the activation of RII-Smad3 signaling ameliorated podocyte injuries in Smad3-knockout diabetic mice. The bone morphogenetic protein 4 (BMP4) significantly regulated activation of RII-Smad3 signalings (P<0.05). Moreover, the epithelium-specific transcription factor, Elf3was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Smad3 signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys. Moreover, AGE treatment induced the secretion of Elf3-containing exosomes from cultured podocytes, which was dependent on the activation of the TGF-β-Smad3 signaling pathway. In addition, exosomal Elf3 protein in urine could be measured only in urinary exosomes from patients with DN. The appearance of urinary exosomal Elf3 protein in patients with DN suggested the existence of irreversible injuries in podocytes. The rate of decline in the estimated Glomerular Filtration Rate (eGFR) after measurement of urinary exosomal Elf3 protein levels in patients with DN (R2 = 0.7259) might be useful as an early non-invasive marker for podocyte injuries in DN.
藤田 結衣, 冨永 辰也, 寒川 裕未, 長井 幸二郎, 安部 秀斉, 土井 俊夫 : BMP4 regulates both podocyte injury and mesangial expansion in the diabetic nephropathy, 四国医学雑誌, Vol.75, No.1-2, 55-62, 2019年.
(要約)
Podocyte injury and loss have been indicated as constituting the crucial pathogenesis of glomerular injury ; however, it remains necessary to elucidate the detailed molecular mechanisms and cell-to-cell response because multiple factors may cause podocyte injury. In the glomerulus, three kinds of cells (endothelial, mesangial, and parietal epithelial) react to podocyte injury. Endothelial and mesangial cells are connected with podocyte cells across the glomerular basement membrane. However, the detailed mechanisms regarding the interaction of the mesangium and podocyte injury are unclear. Diabetic nephropathy is characterized by mesangial matrix expansion caused by an excessive deposition of extracellular matrix proteins in the mesangial area, which can be observed through the increased expression of type IV collagen. We have shown that bone morphogenetic protein 4 (BMP4) signaling leads to the glomerular changes characteristic of this disorder. To analyze the effect of BMP4 was investigated in vitro and in vivo using streptozotocin (STZ)-induced and Bmp4 heterozygous knockout (Bmp4+/-) diabetic mice or podocyte-specific Bmp4 knockout mice, and Bmp4-induced or podocyte-specific transgenic mice. BMP4 positive area and mesangial area fraction showed positively correlation. Furthermore, mesangial area fraction was significantly and negatively correlated with,WT1-positive cell number, and nephrin-positive area. We also demonstrated that the induction of podocyte apoptosis by BMP4 may be mediated by p38 activation and that of caspase 3 through cleavage. In mesangial cells, BMP4 stimulation also induced phosphorylation of p38 and Smad1 and increased cleaved caspase 3, with similar significant inhibition of Smad1 activation and decreased cleaved caspase 3 mediated by dorsomorphin. These data suggest that the BMP4 signaling pathway plays important roles for the development of both podocyte injury and mesangial expansion in diabetic nephropathy.
Taichi Murakami, Masanori Tamaki, Seiji Kishi, Kojiro Nagai, Hideharu Abe, Yoshimi Bando, Yuko Toyoda, Hirokazu Ogino, Yasuhiko Nishioka, Sayo Ueda, Toshio Doi and Motokazu Matsuura : Systemic Sarcoidosis Presenting with Renal Involvement Caused by Various Sarcoidosis-associated Pathophysiological Conditions, Internal Medicine, Vol.58, No.5, 679-684, 2019.
(要約)
A 61-year-old man was diagnosed with sarcoidosis involving the lungs, eyes, parotid gland and extrathoracic lymph nodes complicated by chronic kidney injury and hypercalcemia. Kidney biopsy showed non-specific interstitial nephritis and nephrosclerosis. However, immunohistochemical staining of cell surface markers revealed a multinucleated giant macrophage surrounded by T-cells, suggesting granulomatous interstitial nephritis. Corticosteroid improved the kidney function, and reduced the serum levels of calcium and angiotensin-converting enzyme. Sarcoid nephropathy may be caused by the combination of several sarcoidosis-associated pathophysiological conditions and a comprehensive kidney examination should be performed to assess the type of injury when determining a treatment strategy.
Sayo Ueda, Kojiro Nagai, Narushi Yokota, Daisuke Hirose, Hiroaki Mori, Yoshihiko Noma, Toshio Doi and Jun Minakuchi : Influence of albumin leakage on glycated albumin in patients with type 2 diabetes undergoing hemodialysis., Journal of Artificial Organs, Vol.22, No.3, 264-267, 2019.
(要約)
Glycated albumin (GA) is recommended as a better glycemic indicator than HbA1c in patients undergoing hemodialysis, because the red blood cell lifespan is generally faster than that in normal subjects. However, GA can be also affected by protein loss in urine and hemodialysis fluid. Therefore, in this study, we investigated the effect of albumin leakage induced by hemodialysis on GA. Nine patients undergoing hemodialysis with a large or small amount of albumin leakage were observed for 9 months in a crossover manner. As a result, it was shown that albumin leakage could affect GA, but the effect was practically small considering the prescription of diabetic drugs. The correlations between HbA1c and blood glucose levels and between GA and blood glucose levels were similar in our study. In conclusion, GA was a reliable indicator, even with the change of hemodialysis modality. The influence of albumin leakage induced by hemodialysis on GA was negligible practically. We should recognize that the preferable glycemic indicator in patients undergoing hemodialysis depends on the hemoglobin and albumin metabolism of each patient.
Fumiaki Obata, Hideharu Abe, Taichi Murakami, Sayo Ueda, Taizo Inagaki, Masanori Minato, Hiroyuki Ono, Kenji Nishimura, Eriko Shibata, Masanori Tamaki, Fumi Kishi, Seiji Kishi, Kojiro Nagai and Toshio Doi : Direct oral anticoagulant successfully used to treat an adult nephrotic patient complicated with portal vein thrombosis., CEN Case Reports, Vol.8, No.2, 134-138, 2019.
(要約)
Thromboembolism is a major complication of nephrotic syndrome, with the renal vein being the most frequent site. However, the incidence of portal vein thrombosis (PVT) in patients with nephrotic syndrome is rare. We report a case of a relapsed steroid-dependent minimal change disease with incidental PVT. A 38-year-old man presented with anasarca. Elevated liver enzymes were discovered during routine blood testing within days after commencing treatment. Although drug-induced liver injuries are frequently observed with mild aminotransferase abnormality during therapy with steroid or immune-suppressive agents, imaging revealed a massive thrombus of the portal vein, which was treated by anticoagulant therapy with edoxaban. Treatment with anticoagulant therapy could normalize liver function. Two months after the initiation of treatment with edoxaban, the follow-up CT scan and ultrasound showed the disappearance of PVT. Our case suggests that much attention should be paid to PVT as a cause of liver enzyme elevation when treating patients with nephrotic syndrome.
Hideharu Abe and Toshio Doi : A New Insight into Molecular Function of Smads Signalings in Diabetic Nephropathy., Advanced Techniques in Biology & Medicine, Vol.7, No.1, 2019.
Masanori Tamaki, Tatsuya Tominaga, Yui Fujita, Yasuhiko Koezuka, Go Ichien, Taichi Murakami, Seiji Kishi, Keiichi Yamamoto, Hideharu Abe, Kojiro Nagai and Toshio Doi : All-trans retinoic acid suppresses bone morphogenetic protein 4 in mouse diabetic nephropathy through a unique retinoic acid response element., American Journal of Physiology, Endocrinology and Metabolism, Vol.316, No.3, E418-E431, 2019.
(要約)
Diabetic nephropathy (DN) causes mesangial matrix expansion, which results in glomerulosclerosis and renal failure. Collagen IV (COL4) is a major component of the mesangial matrix that is positively regulated by bone morphogenetic protein 4 (BMP4)/suppressor of mothers against decapentaplegic (Smad1) signaling. Because previous studies showed that retinoids treatment had a beneficial effect on kidney disease, we investigated the therapeutic potential of retinoids in DN, focusing especially on the regulatory mechanism of BMP4. Diabetes was induced with streptozotocin in 12-wk-old male Crl:CD1(ICR) mice, and, 1 mo later, we initiated intraperitoneal injection of all-trans retinoic acid (ATRA) three times weekly. Glomerular matrix expansion, which was associated with increased BMP4, phosphorylated Smad1, and COL4 expression, worsened in diabetic mice at 24 wk of age. ATRA administration alleviated DN and downregulated BMP4, phosopho-Smad1, and COL4. In cultured mouse mesangial cells, treatment with ATRA or a retinoic acid receptor-α (RARα) agonist significantly decreased BMP4 and COL4 expression. Genomic analysis suggested two putative retinoic acid response elements (RAREs) for the mouse Bmp4 gene. Chromatin immunoprecipitation analysis and reporter assays indicated a putative RARE of the Bmp4 gene, located 11,488-11,501 bp upstream of exon 1A and bound to RARα and retinoid X receptor (RXR), which suppressed BMP4 expression after ATRA addition. ATRA suppressed BMP4 via binding of a RARα/RXR heterodimer to a unique RARE, alleviating glomerular matrix expansion in diabetic mice. These findings provide a novel regulatory mechanism for treatment of DN.
Eriko Shibata, Kojiro Nagai, Sayo Ueda, Hiroyuki Ono, Kenji Nishimura, Taizo Inagaki, Masanori Minato, Fumi Kishi, Masanori Tamaki, Taichi Murakami, Seiji Kishi, Hideharu Abe, Narushi Yokota, Jun Minakuchi and Toshio Doi : The utility and limitation of inferior vena cava diameter as a dry weight marker., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 172-177, 2019.
(要約)
IVCdexp was a rough marker to estimate volume status and only useful in suggesting apparent hypervolemia or hypovolemia. We should know that the IVCdexp value is affected by a lotof factors and not a definitive marker for estimating practical DW. J. Med. Invest. 66 : 172-177, February, 2019.
Tatsuya Tominaga, Isha Sharma, Yui Fujita, Toshio Doi, K Aryana Wallner and S Yashpal Kanwar : Myo-inositol oxygenase accentuates renal tubular injury initiated by endoplasmic reticulum stress., American Journal of Physiology, Renal Physiology, Vol.316, No.2, F301-F315, 2018.
(要約)
Besides oxidant stress, endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of various metabolic disorders affecting the kidney. These two forms of stresses are not mutually exclusive to each other and may operate by a feedback loop in worsening the cellular injury. To attest to this contention, studies were performed to assess whether in such a setting, there is worsening of tubulointerstitial injury. We employed tunicamycin as a model of ER stress and used tubular cells and mice overexpressing myo-inositol oxygenase (MIOX), an enzyme involved in glycolytic events with excessive generation of ROS. Concomitant treatment of tunicamycin and transfection of cells with MIOX-pcDNA led to a marked generation of ROS, which was reduced by MIOX-siRNA. Likewise, an accentuated expression of ER stress sensors, GRP78, XBP1, and CHOP, was observed, which was reduced with MIOX-siRNA. These sensors were markedly elevated in MIOX-TG mice compared with WT treated with tunicamycin. This was accompanied with marked deterioration of tubular morphology, along with impairment of renal functions. Interestingly, minimal damage and elevation of ER stressors was observed in MIOX-KO mice. Downstream events that were more adversely affected in MIOX-TG mice included accentuated expression of proapoptogenic proteins, proinflammatory cytokines, and extracellular matrix constituents, although expression of these molecules was unaffected in MIOX-KO mice. Also, their tunicamycin-induced accentuated expression in tubular cells was notably reduced with MIOX-siRNA. These studies suggest that the biology of MIOX-induced oxidant stress and tunicamycin-induced ER stress are interlinked, and both of the events may feed into each other to amplify the tubulointerstitial injury.
Yui Fujita, Tatsuya Tominaga, Hideharu Abe, Yumi Kangawa, Naoshi Fukushima, Otoya Ueda, Kou-Ichi Jishage, Seiji Kishi, Taichi Murakami, Yumiko Saga, S Yashpal Kanwar, Kojiro Nagai and Toshio Doi : An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury., Scientific Reports, Vol.8, No.1, 2018.
(要約)
Podocyte injury has been proposed to play an important role in diabetic nephropathy; however, its pathological mechanism remains unclear. We have shown that bone morphogenetic protein 4 (BMP4) signaling leads to the glomerular changes characteristic of this disorder. To analyze the molecular mechanism of podocyte injury, the effect of BMP4 was investigated using streptozotocin (STZ)-induced, Bmp4 heterozygous knockout (Bmp4+/-) and podocyte-specific Bmp4 knockout mice. Mice with STZ-induced diabetes exhibited glomerular matrix hyperplasia and decreased numbers of podocyte nucleus-specific WT1-positive cells. The number of podocytes and proteinuria were improved in both diabetic Bmp4 knockout mouse models compared to the effects observed in the control mice. The effect of BMP4 overexpression on Bmp4-induced or podocyte-specific transgenic mice was examined. Tamoxifen-induced Bmp4-overexpressing mice exhibited mesangial matrix expansion and decreased numbers of WT1-positive cells. Podocyte-specific Bmp4-overexpressing mice displayed increased kidney BMP4 expression and mesangial matrix expansion but decreased nephrin expression and numbers of WT1-positive cells. Both lines of Bmp4-overexpressing mice exhibited increased albuminuria. In cultured podocytes, BMP4 increased phospho-p38 levels. BMP4 decreased nephrin expression but increased cleaved caspase-3 levels. p38 suppression inhibited caspase-3 activation. Apoptosis was confirmed in STZ-diabetic glomeruli and Bmp4-overexpressing mice. Bmp4 +/- mice with diabetes displayed reduced apoptosis. Based on these data, the BMP4 signaling pathway plays important roles in the development of both podocyte injury and mesangial matrix expansion in diabetic nephropathy.
Hideharu Abe, Akiko Sakurai, Hiroyuki Ono, Sanae Hayashi, Sakiya Yoshimoto, Arisa Ochi, Sayo Ueda, Kenji Nishimura, Eriko Shibata, Masanori Tamaki, Fumi Kishi, Seiji Kishi, Taichi Murakami, Kojiro Nagai and Toshio Doi : Urinary Exosomal mRNA of WT1 as Diagnostic and Prognostic Biomarker for Diabetic Nephropathy, The Journal of Medical Investigation : JMI, Vol.65, No.3.4, 208-215, 2018.
(要約)
Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality as compared to other causes of renal disease. Albuminuria is often the first clinical indicator of the presence of DN. However, albuminuria or proteinuria is a common symptom in patients with various renal disorders. Therefore, specific biomarkers for the diagnosis of DN are required. A primary hallmark of DN is the progressive damage and death of glomerular podocytes, resulting in the leaking of proteins into the urine. Urinary exosomes released by podocytes are microvesicles containing information of the originated cells. Podocyte-derived signal transduction factors (PDSTFs) are good candidates to assess podocyte injuries. The profile of PDSTFs in urinary exosomes from patients with DN is different from that from patients with minimal change nehrotic syndrome. In addition, PDSTFs molecules in exosomes were derived from primary murine podocytes under high glucose conditions. Among PDSTFs in urinary exosomes, Wilms tumor 1 (WT1) levels reflected damage of diabetic glomeruli in the patients. Urinary exosomal WT1 can predict the decline in eGFR for the following several years. In conclusion, urinary exosomal WT1 is a useful biomarker to improve risk stratification in patients with DN. J. Med. Invest. 65:208-215, August, 2018.
Hiroyuki Ono, Hideharu Abe, Akiko Sakurai, Arisa Ochi, Tatsuya Tominaga, Masanori Tamaki, Seiji Kishi, Taichi Murakami, Kojiro Nagai, Masayuki Kohashi and Toshio Doi : Novel Interplay Between Smad1 and Smad3 Phosphorylation via AGE Regulates the Progression of Diabetic Nephropathy., Scientific Reports, Vol.8, No.1, 2018.
(要約)
; db/db mice and probucol-treated db/db mice, which was consistent with the attenuation of ECM overproduction. These results indicate that Smad3 expression and activation or probucol treatment alters Smad1 phosphorylation, thus suggesting new molecular mechanisms underlying DN development and progression.
Seiji Kishi, Masanori Minato, Atsuro Saijo, Naoka Murakami, Masanori Tamaki, Motokazu Matsuura, Taichi Murakami, Kojiro Nagai, Hideharu Abe, Yasuhiko Nishioka and Toshio Doi : IgA Nephropathy after Nivolumab Therapy for Postoperative Recurrence of Lung Squamous Cell Carcinoma., Internal Medicine, Vol.57, No.9, 1259-1263, 2018.
(要約)
Immune checkpoint inhibitors (ICIs) are becoming a common and important cancer therapy. ICIs are associated with a unique category of side effects, termed immune-related adverse events (irAEs). We herein report the case of a 72-year-old man with postoperative recurrence of lung squamous cell carcinoma who was treated with nivolumab and who developed proteinuria and a worsening kidney function. A kidney biopsy revealed IgA nephropathy. After drug withdrawal, the proteinuria improved and the deterioration of the patient's renal function was halted. Although renal irAEs are considered to be rare and glomerulonephritis is not typical presentation, physicians need to pay more attention to renal irAEs and glomerular injury.
Kojiro Nagai, Hiroyuki Ono, Motokazu Matsuura, Michael Hann, Sayo Ueda, Sakiya Yoshimoto, Masanori Tamaki, Taichi Murakami, Hideharu Abe, Hisashi Ishikura and Toshio Doi : Progressive renal insufficiency related to ALK inhibitor, alectinib., Oxford Medical Case Reports, Vol.2018, No.4, 2018.
(要約)
Alectinib is a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor and is generally effective and tolerated in patients who have demonstrated disease progression or adverse effects while on the first generation inhibitor, crizotinib. ALK inhibitors can cause a reversible chronic increase of serum creatinine concentration; however, they rarely induce progressive renal insufficiency. We herein report a case of a 68-year-old woman diagnosed with ALK-positive advanced non-small cell lung cancer and who received ALK inhibitors. Due to dysgeusia and transaminitis, her medication was switched from crizotinib to alectinib. Rapid progressive glomerulonephritis developed 1 year after the initiation of alectinib treatment. A renal biopsy revealed unique kidney lesions in both tubules and glomeruli. Glucocorticoid therapy partially reversed kidney impairment. However, re-administration of alectinib caused kidney dysfunction, which was improved by the cessation of alectinib. Our case suggests that much attention should be paid to kidney function when using ALK inhibitors.
Fumi Kishi, Kojiro Nagai, Norimichi Takamatsu, Tatsuya Tominaga, Masanori Tamaki, E. Shibata, Taichi Murakami, Seiji Kishi, Hideharu Abe, Y Koezuka, N Minagawa, G Ichien and Toshio Doi : Urinary type IV collagen excretion is involved in the decline in estimated glomerular filtration rate in the Japanese general population without diabetes: A 5-year observational study., PLoS ONE, Vol.13, No.4, e0195523, 2018.
(要約)
Urinary type IV collagen (U-Col4) and albumin excretion is evaluated to monitor the development of diabetic kidney disease. However, U-Col4 excretion in the general population without diabetes has not yet been fully elucidated. In this study, 1067 participants without diabetes and with urinary albumin-creatinine ratio <300 mg/gCr (normo- or microalbuminuria) who underwent an annual health examination in 2004 were enrolled and observed for 5 years. They were divided according to the amount of U-Col4 or urinary albumin excreted. The decline in estimated glomerular filtration rate (eGFR) was calculated. In participants with eGFR ≥80 mL/min, abnormal U-Col4 excretion was indicated as a significant independent risk factor for 10% eGFR change per year, which is one of the prognostic factors for the development of end-stage kidney disease. Moreover, in contrast to urinary albumin excretion, U-Col4 excretion was not related to age or kidney function, suggesting that some individuals with abnormal U-Col4 excretion can have an independent hidden risk for the development of kidney dysfunction. In conclusion, it is important to measure U-Col4 excretion in the general population without diabetes to determine changes in renal features in every individual and help detect future complications such as diabetic kidney disease. If U-Col4 excretion is abnormal, kidney manifestation should be carefully followed up, even if the kidney function and urinalysis findings are normal.
(キーワード)
Adult / Aged / Aged, 80 and over / Albuminuria / Asian Continental Ancestry Group / Collagen Type IV / Diabetic Nephropathies / Disease Progression / Female / Glomerular Filtration Rate / Humans / Japan / Kaplan-Meier Estimate / Male / Middle Aged / Prognosis / Renal Insufficiency / Risk Factors / Young Adult
Toshio Doi, Hideharu Abe, Seiji Kishi, Taichi Murakami, Kojiro Nagai and Tatsuya Tominaga : Urinary IgG4 and Smad1 are Specific Biomarkers for Renal Structural and Functional Changes in Early Stages of Diabetic Nephropathy., Diabetes, Vol.67, No.5, 986-993, 2018.
(要約)
Diabetic nephropathy (DN) is the major cause of end-stage kidney disease, but early biomarkers of DN risk are limited. Herein we examine urinary IgG4 and Smad1 as additional early DN biomarkers. We recruited 815 patients with type 2 diabetes; 554 patients fulfilled the criteria of an estimated glomerular filtration rate (eGFR) >60 mL/min and no macroalbuminuria at baseline, with follow-up for 5 years. Patients without macroalbuminuria were also recruited for renal biopsies. Urinary IgG4 and Smad1 were determined by enzyme-linked immunoassays using specific antibodies. The specificity, sensitivity, and reproducibility were confirmed for each assay. Increased urinary IgG4 was significantly associated with lower eGFR. The level of urinary IgG4 also significantly correlated with surface density of peripheral glomerular basement membrane (Sv PGBM/Glom), whereas Smad1 was associated with the degree of mesangial expansion-both classic pathological findings in DN. Baseline eGFR did not differ between any groups; however, increases in both urinary IgG4 and Smad1 levels at baseline significantly predicted later development of eGFR decline in patients without macroalbuminuria. These data suggest that urinary IgG4 and Smad1 at relatively early stages of DN reflect underlying DN lesions and are relevant to later clinical outcomes.
(キーワード)
Adult / Biomarkers / Diabetes Mellitus, Type 2 / Diabetic Nephropathies / Early Diagnosis / Enzyme-Linked Immunosorbent Assay / Female / Glomerular Basement Membrane / Glomerular Filtration Rate / Humans / Immunoglobulin G / Kidney / Male / Mesangial Cells / Microscopy, Electron / Middle Aged / Reproducibility of Results / Sensitivity and Specificity / Smad1 Protein
Kojiro Nagai, Sayo Ueda, Kenji Tsuchida, Toshio Doi and Jun MInakuchi : Low serum sodium concentration is a prognostic factor related to current blood glucose level in stable hemodialysis patients: an observational study., Renal Replacement Therapy, Vol.3, 55, 2017.
Kojiro Nagai, Motokazu Matsuura, Kenji Tsuchida, Hiro-omi Kanayama, Toshio Doi and Jun Minakuchi : Prognostic factors for mortality in middle-aged and older hemodialysis patients: a 5-year observational study., Journal of Artificial Organs, Vol.21, No.1, 94-101, 2017.
(要約)
Clinical guidelines for hemodialysis therapy have been described in an evidence-based manner with most evidence from randomized control trials or retrospective studies in which all generations of the hemodialysis patients were enrolled. Therefore, the question still remains whether these guidelines can be applied to increasing older patients. This study is an observational study, including 735 patients who received maintenance hemodialysis in April 2006. At baseline, the participants' age was 62.1 ± 12.8 years (mean ± SD). Hemodialysis duration was 103.7 ± 89.3 months. In a 5-year observation period (actual follow-up period: 1551 ± 499 days), 175 patients died. Prognostic factors were investigated by multivariate analysis with Cox proportional hazard model. Next, we stratified the patients according to their age. 363 patients were included in the middle-aged patient's category between 40 and 64 years, and 314 were involved in the older patient's category between 65 and 84 years old. As a subanalysis, significant predictors of 5-year survival were examined in the age-stratified cohort. Then, Kt/V, serum β
Hiroyuki Ono, Kojiro Nagai, Eriko Shibata, Motokazu Matsuura, Seiji Kishi, Taizo Inagaki, Masanori Minato, Sakiya Yoshimoto, Sayo Ueda, Fumiaki Obata, Kenji Nishimura, Masanori Tamaki, Fumi Kishi, Taichi Murakami, Hideharu Abe, Yukiko Kinoshita, Maki Urushihara, Shoji Kagami and Toshio Doi : Re-recognition of Age-dependent Reference Range for the Serum Creatinine Level in Teenagers - A Case of Slowly Progressive Tubulointerstitial Nephritis which Occurred in an Adolescent., Internal Medicine, Vol.56, No.16, 2187-2193, 2017.
(要約)
For the first time, a 15-year-old boy was found to have a slight degree of proteinuria and microscopic hematuria during annual school urinalysis screening. His kidney function had already severely deteriorated. A kidney biopsy revealed tubulointerstitial nephritis (TIN) with diffuse inflammatory cell infiltration. His medical records showed his serum creatinine level to be 0.98 mg/dL two years ago, which was abnormally high considering his age. Although the etiology of slowly progressive TIN was unclear, glucocorticoid and immunosuppressant therapy improved his kidney function. This case report suggests that all doctors should recognize the reference range for the serum creatinine level in teenagers.
Hiroyuki Ono, Taichi Murakami, Akira Mima, Eriko Shibata, Masanori Tamaki, Sakiya Yoshimoto, Sayo Ueda, Fumi Kishi, Seiji Kishi, Takashi Kawanaka, Motokazu Matsuura, Kojiro Nagai, Hideharu Abe, Masashi Harada and Toshio Doi : Successful treatment of highly advanced immunoglobulin G4-related kidney disease presenting renal mass-like regions with end-stage kidney failure: a case study., BMC Nephrology, Vol.18, No.1, 261, 2017.
(要約)
A 59-year-old Japanese man was referred to our hospital because of uremia with a creatinine level of 12.36 mg/dL. Urinalysis revealed mild proteinuria and hyperβ2microglobulinuria, and blood tests showed hyperglobulinemia with an IgG level of 3243 mg/dL and an IgG4 level of 621 mg/dL. Non-contrast computed tomography revealed renal mass-like regions. Based on the findings, immunoglobulin G4-related kidney disease was suspected, however, further radiological examination showed unexpected results. Ga-67 scintigraphy showed no kidney uptake. T2-weighted magnetic resonance imaging revealed high-intensity signals which corresponded to mass-like regions and multiple patchy low-intensity signals in kidney cortex. Finally, the patient was diagnosed with immunoglobulin G4-related kidney disease by renal pathology of severe immunoglobulin G4-positive plasma cell-rich tubulointerstitial nephritis and characteristic fibrosis. He received 50 mg oral prednisolone, which was tapered with a subsequent decrease of serum creatinine and IgG4 levels. One year after initiation of treatment, he achieved normalization of serum IgG4 level and proteinuria, and remained off dialysis with a creatinine level of 3.50 mg/dL. After treatment with steroids, repeat imaging suggested bilateral severe focal atrophy. However, mass-like regions did not show atrophic change although renal atrophy was evident in patchy low-intensity lesions on T2-weighted magnetic resonance imaging. These findings suggest that multiple patchy low-intensity signals and high-intensity mass-like regions were mildly atrophic lesions of immunoglobulin G4-related kidney disease due to severe fibrosis and normal parts of kidney, respectively.
Kojiro Nagai, Tatsuya Tominaga, Sayo Ueda, Eriko Shibata, Masanori Tamaki, Motokazu Matsuura, Seiji Kishi, Taichi Murakami, Tatsumi Moriya, Hideharu Abe and Toshio Doi : Mesangial Cell Mammalian Target of Rapamycin Complex 1 Activation Results in Mesangial Expansion., Journal of the American Society of Nephrology, Vol.28, No.10, 2879-2885, 2017.
(要約)
Human glomerular diseases can be caused by several different diseases, many of which include mesangial expansion and/or proliferation followed by glomerulosclerosis. However, molecular mechanisms underlying the pathologic mesangial changes remain poorly understood. Here, we investigated the role of the mammalian target of rapamycin complex 1 (mTORC1)-S6 kinase pathway in mesangial expansion and/or proliferation by ablating an upstream negative regulator, tuberous sclerosis complex 1 (TSC1), using tamoxifen-induced Foxd1-Cre mice [Foxd1ER(+) TSC1 mice]. Foxd1ER(+) TSC1 mice showed mesangial expansion with increased production of collagen IV, collagen I, and -smooth muscle actin in glomeruli, but did not exhibit significant mesangial proliferation or albuminuria. Furthermore, rapamycin treatment of Foxd1ER(+) TSC1 mice suppressed mesangial expansion. Among biopsy specimens from patients with glomerular diseases, analysis of phosphorylated ribosomal protein S6 revealed mesangial cell mTORC1 activation in IgA nephropathy and in lupus mesangial proliferative nephritis but not in the early phase of diabetic nephropathy. In summary, mesangial cell mTORC1 activation can cause mesangial expansion and has clinical relevance for human glomerular diseases. This report also confirms that the tamoxifen-induced mesangium-specific Cre-loxP system is useful for studies designed to clarify the role of the mesangium in glomerular diseases in adults.
Hiroyuki Ono, Seiji Kishi, Taizo Inagaki, Masako Mizusawa, Taichi Murakami, Kojiro Nagai, Hideharu Abe and Toshio Doi : Shunt nephritis and pyogenic spondylitis with a positive PR3-ANCA associated with chronically infected ventriculo-atrial shunt, Kidney International Reports, Vol.2, No.4, 774-778, 2017.
Kojiro Nagai, Kenji Tsuchida, Noriyuki Ishihara, Naoto Minagawa, Go Ichien, Satoshi Yamada, Daisuke Hirose, Hiroyuki Michiwaki, Hiro-omi Kanayama, Toshio Doi and Jun Minakuchi : Implications of Albumin Leakage for Survival in Maintenance Hemodialysis Patients: A 7-year Observational Study., Therapeutic Apheresis and Dialysis, 2017.
(要約)
Albumin leakage during hemodialysis (HD) presents a clinical dilemma. However, protein-binding uremic toxins are suggested to be responsible for increased mortality. No one has investigated the relationship between albumin leakage and mortality. Therefore, the purpose of this observational study was to analyze the association of albumin leakage with mortality in 690 HD patients who survived one year after enrollment. They were divided to three groups who received HD with large (3 g or more per HD session), middle (1 to 3 g) or small (less than 1 g) amount of albumin leakage, respectively. A propensity score analysis minimizing indication bias was performed. Consequently, in a 7-year observation period, 212 patients died. Albumin leakage 3 g or more per HD session provided better prognosis than albumin leakage less than 3 g per HD session. In conclusion, clinically acceptable large albumin leakage provides beneficial effects on mortality in maintenance HD patients.
Hideharu Abe, Akiko Sakurai and Toshio Doi : Probucol modulates Nrf2 function and ameliorates diabetic nephropathy in db/db mice., Medical Research Archives, Vol.10, No.4, 1-16, 2017.
Motokazu Matsuura, Hideharu Abe, Tatsuya Tominaga, Akiko Sakurai, Taichi Murakami, Seiji Kishi, Yoshimi Bando, Jun Minakuchi, Kojiro Nagai and Toshio Doi : A Novel Method of DAPI Staining for Differential Diagnosis of Renal Amyloidosis., The Journal of Medical Investigation : JMI, Vol.64, No.3.4, 217-221, 2017.
(要約)
Amyloidosis is often overlooked because its clinical manifestations can mimic those of more-common diseases. It is important to get a precise diagnosis as early as possible for the prevention of further organ damages. Amyloidosis is a disorder caused by deposition of insoluble abnormal amyloid. The kidney is a frequent site of amyloid deposition. The amyloid fibrils have a characteristic appearance and generate birefringence under polarized light when stained with the Congo red dye. Classification of amyloidosis is based on the precursor protein that forms the amyloid fibrils and the distribution of amyloid deposits as either systemic or localized. Involvement of amyloid fibrils in kidneys mainly occurs as amyloid light-chain (AL) or amyloid A (AA) amyloidosis. The potassium permanganate method with Congo red staining was once used widely to discriminate AL and AA amyloidoses, but this method has a problem of false positive results. We found that extracellular and cytoplasmic glomerular 4', 6-diamidino-2-phenylindole (DAPI)-positive areas were clearly consistent with amyloid deposition in AL amyloidosis. In contrast, the overlapping staining was not seen in AA amyloidosis. Therefore, we propose that DAPI staining readily distinguishes AL renal amyloidosis from AA renal amyloidosis as a simple and reproducible histochemical method. J. Med. Invest. 64: 217-221, August, 2017.
(キーワード)
Amyloidosis / Kidney Diseases / Serum Amyloid A Protein / Staining and Labeling
Sakiya Yoshimoto, Kojiro Nagai, Eriko Shibata, Sayo Ueda, Hiroyuki Ono, Masanori Tamaki, Kenji Nishimura, Fumiaki Obata, Taizo Inagaki, Masanori Minato, Fumi Kishi, Motokazu Matsuura, Naoko Matsui, Itsuro Endo, Michael Hann, Seiji Kishi, Taichi Murakami, Hideharu Abe and Toshio Doi : Influential factors on serum albumin concentration in hospitalized chronic kidney disease patients., The Journal of Medical Investigation : JMI, Vol.64, No.1.2, 146-152, 2017.
(要約)
SAC was affected by not only proteinuria, but also postural change, physical activity, and food in CKD patients. SAC should be analyzed by standardizing a patient's condition during phlebotomy. J. Med. Invest. 64: 146-152, February, 2017.
Fumiaki Obata, Taichi Murakami, Junko Miyagi, Sayo Ueda, Taizo Inagaki, Masanori Minato, Hiroyuki Ono, Kenji Nishimura, Eriko Shibata, Masanori Tamaki, Sakiya Yoshimoto, Fumi Kishi, Seiji Kishi, Motokazu Matsuura, Kojiro Nagai, Hideharu Abe and Toshio Doi : A case of rapid amelioration of hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis treated by interferon-free directly acting antivirals for HCV in the absence of immunosuppressant., CEN Case Reports, Vol.6, No.1, 55-60, 2016.
(要約)
Mixed cryoglobulinemic syndrome, which is a systemic vasculitis characterized by the immune complex deposition in small- and medium-sized arteries and most often due to chronic hepatitis C virus (HCV) infection, sometimes clinically manifests as refractory glomerulonephritis or nephritic syndrome. Patients with mixed cryoglobulinemic nephropathy who have a rapidly progressive glomerulonephritis should receive immunosuppressive therapy. After disease stabilization, patients should receive concurrent therapy for the underlying HCV infection. The standard therapy of a chronic HCV infection is IFN monotherapy or IFN combined with ribavirin; however, after the introduction of direct-acting antivirals (DAAs), the standard therapy for patients with HCV genotype 1 has dramatically changed. We report a case of HCV-associated cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) successfully treated by daclatasvir and asunaprevir, which are IFN-free DAAs for HCV, in combination with angiotensin II receptor blocker without immunosuppressive therapy. The patient developed severe nephrotic syndrome with progressive kidney dysfunction. Blood examination revealed a high copy number of HCV-RNA (6.4 log IU/mL, type 1), cryoglobulinemia, paraproteinemia of IgM-, and hypocomplementemia. Histological analysis showed MPGN type 1. These findings were compatible with those observed in HCV-associated cryoglobulinemic MPGN. This case offers original evidence for the application of newer generation of IFN-free DAAs in the treatment of HCV-associated cryoglobulinemic nephropathy.
Yuko Toyoda, Ryohiko Ozaki, Jun Kishi, Masaki Hanibuchi, Katsuhiro Kinoshita, Toshifumi Tezuka, Hisatsugu Goto, Hiroyuki Ono, Kojiro Nagai, Yoshimi Bando, Toshio Doi and Yasuhiko Nishioka : An Autopsy Case of Aortic Intimal Sarcoma Initially Diagnosed as Polyarteritis Nodosa., Internal Medicine, Vol.55, No.21, 3191-3195, 2016.
(要約)
A 61-year-old man had hypertension with stenosis in the left renal artery. When his fever, abdominal pain, and renal dysfunction progressed, he was admitted to our hospital. He was diagnosed with polyarthritis nodosa. His renal function rapidly deteriorated despite immunosuppressive therapy. His digestive tract perforated twice, and he subsequently died. An autopsy revealed that aortic intimal sarcoma caused stenosis in multiple arteries. Both polyarteritis nodosa and aortic intimal sarcoma are very rare diseases and the diagnoses are very difficult. It is very important to consider these entities when making a differential diagnosis of vasculitis.
Kojiro Nagai, Kenji Tsuchida, Daisuke Hirose, Hiroyuki Michiwaki, Michael Hann, Hiro-omi Kanayama, Toshio Doi and Jun Minakuchi : The effect of albumin leakage in hemodialysis patients on redox status of serum albumin., Journal of Artificial Organs, 2016.
(要約)
Human mercaptoalbumin (HMA) is a reduced form of albumin that is associated with cardiovascular disease in dialysis patients. Albumin-leaky hemodialysis (HD) is increasingly recognized as a gold standard therapy because it is correlated with better prognosis compared to conventional HD. However, albumin-leaky HD induces low serum albumin concentration because of albumin leakage, which is a classical risk factor for mortality. The aim of this study was to explain the preferable prognosis in patients undergoing albumin-leaky HD with low serum albumin concentration. Ten HD patients were enrolled. They were preconditioned with albumin-non-leaky HD (mean albumin leakage: 1.0 g) for 2 months. Subsequently, albumin-leaky HD (9.1 g) was performed for 6 months, followed by relatively non-leaky HD (within 3.0 g). The ratio and level of HMA were evaluated. The amount of albumin leakage was related to the ratio of HMA, and inversely correlated with serum albumin concentration. The level of HMA was maintained regardless of albumin leakage. Regarding HMA level, a moderate amount of albumin leakage was acceptable. A stably maintained HMA level in albumin-leaky HD patients can contribute to preferable prognosis even if they have low serum albumin concentration.
Tatsuya Tominaga, K Rajesh Dutta, Darukeshwara Joladarashi, Toshio Doi, K Janardan Reddy and S Yashpal Kanwar : Transcriptional and Translational Modulation of myo-Inositol Oxygenase (Miox) by Fatty Acids: IMPLICATIONS IN RENAL TUBULAR INJURY INDUCED IN OBESITY AND DIABETES., The Journal of Biological Chemistry, Vol.291, No.3, 1348-1367, 2015.
(要約)
The kidney is one of the target organs for various metabolic diseases, including diabetes, metabolic syndrome, and obesity. Most of the metabolic studies underscore glomerular pathobiology, although the tubulo-interstitial compartment has been underemphasized. This study highlights mechanisms concerning the pathobiology of tubular injury in the context of myo-inositol oxygenase (Miox), a tubular enzyme. The kidneys of mice fed a high fat diet (HFD) had increased Miox expression and activity, and the latter was related to phosphorylation of serine/threonine residues. Also, expression of sterol regulatory element-binding protein1 (Srebp1) and markers of cellular/nuclear damage was increased along with accentuated apoptosis and loss of tubular brush border. Similar results were observed in cells treated with palmitate/BSA. Multiple sterol-response elements and E-box motifs were found in the miox promoter, and its activity was modulated by palmitate/BSA. Electrophoretic mobility and ChIP assays confirmed binding of Srebp to consensus sequences of the miox promoter. Exposure of palmitate/BSA-treated cells to rapamycin normalized Miox expression and prevented Srebp1 nuclear translocation. In addition, rapamycin treatment reduced p53 expression and apoptosis. Like rapamycin, srebp siRNA reduced Miox expression. Increased expression of Miox was associated with the generation of reactive oxygen species (ROS) in kidney tubules of mice fed an HFD and cell exposed to palmitate/BSA. Both miox and srebp1 siRNAs reduced generation of ROS. Collectively, these findings suggest that HFD or fatty acids modulate transcriptional, translational, and post-translational regulation of Miox expression/activity and underscore Miox being a novel target of the transcription factor Srebp1. Conceivably, activation of the mTORC1/Srebp1/Miox pathway leads to the generation of ROS culminating into tubulo-interstitial injury in states of obesity.
Takahiro Hirano, Taichi Murakami, Hiroyuki Ono, Akiko Sakurai, Tatsuya Tominaga, Toshikazu Takahashi, Kojiro Nagai, Toshio Doi and Hideharu Abe : A Novel Interaction between FLICE-Associated Huge Protein (FLASH) and E2A Regulates Cell Proliferation and Cellular Senescence via Tumor Necrosis Factor (TNF)-Alpha-p21WAF1/CIP1 Axis., PLoS ONE, Vol.10, No.7, e0133205, 2015.
(要約)
Dysregulation of the cell proliferation has been implicated in the pathophysiology of a number of diseases. Cellular senescence limits proliferation of cancer cells, preventing tumorigenesis and restricting tissue damage. However, the role of cellular senescence in proliferative nephritis has not been determined. The proliferative peak in experimental rat nephritis coincided with a peak in E2A expression in the glomeruli. Meanwhile, E12 (an E2A-encoded transcription factor) did not promote proliferation of Mesangial cells (MCs) by itself. We identified caspase-8-binding protein FLICE-associated huge protein (FLASH) as a novel E2A-binding partner by using a yeast two-hybrid screening. Knockdown of FLASH suppressed proliferation of MCs. This inhibitory effect was partially reversed by the knockdown of E2A. In addition, the knockdown of FLASH induced cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) expression, but did not affect p53 expression. Furthermore, overexpression of E12 and E47 induced p21, but not p53 in MCs, in the absence of FLASH. We also demonstrated that E2A and p21 expression at the peak of proliferation was followed by significant induction of FLASH in mesangial areas in rat proliferative glomerulonephritis. Moreover, we revealed that FLASH negatively regulates cellular senescence via the interaction with E12. We also demonstrated that FLASH is involved in the TNF--induced p21 expressions. These results suggest that the functional interaction of E2A and FLASH play an important role in cell proliferation and cellular senescence via regulation of p21 expression in experimental glomerulonephritis.
Kojiro Nagai, Jun Kishi, Shun Morizumi, Jun Minakuchi, Yoshimi Bando, Yasuhiko Nishioka and Toshio Doi : Henoch-Schönlein purpura nephritis occurring postpartum in a patient with anti-PL-7 anti-synthetase syndrome., Modern Rheumatology, Vol.28, 1-4, 2015.
(要約)
A 37-year-old pregnant woman developed purpura which was subsequently diagnosed as Henoch-Schönlein purpura (HSP). After childbirth, the patient developed proteinuria and hematuria. Further examination revealed that the HSP nephritis (HSPN) was associated with anti-threonyl-tRNA synthetase anti-synthetase syndrome. The onset of HSPN during pregnancy or after childbirth is rare. Moreover, to our knowledge, this is the first case to describe renal involvement in anti-synthetase syndrome.
Takeshi Matsubara, Makoto Araki, Hideharu Abe, Otoya Ueda, Kou-Ichi Jishage, Akira Mima, Chisato Goto, Tatsuya Tominaga, Masahiko Kinosaki, Seiji Kishi, Kojiro Nagai, Noriyuki Iehara, Naoshi Fukushima, Toru Kita, Hidenori Arai and Toshio Doi : Bone Morphogenetic Protein 4 and Smad1 Mediate Extracellular Matrix Production in the Development of Diabetic Nephropathy., Diabetes, Vol.64, No.8, 2978-2990, 2015.
(要約)
Diabetic nephropathy is the leading cause of end-stage renal disease. It is pathologically characterized by the accumulation of extracellular matrix in the mesangium, of which the main component is 1/2 type IV collagen (Col4a1/a2). Recently, we identified Smad1 as a direct regulator of Col4a1/a2 under diabetic conditions in vitro. Here, we demonstrate that Smad1 plays a key role in diabetic nephropathy through bone morphogenetic protein 4 (BMP4) in vivo. Smad1-overexpressing mice (Smad1-Tg) were established, and diabetes was induced by streptozotocin. Nondiabetic Smad1-Tg did not exhibit histological changes in the kidney; however, the induction of diabetes resulted in an 1.5-fold greater mesangial expansion, consistent with an increase in glomerular phosphorylated Smad1. To address regulatory factors of Smad1, we determined that BMP4 and its receptor are increased in diabetic glomeruli and that diabetic Smad1-Tg and wild-type mice treated with a BMP4-neutralizing antibody exhibit decreased Smad1 phosphorylation and 40% less mesangial expansion than those treated with control IgG. Furthermore, heterozygous Smad1 knockout mice exhibit attenuated mesangial expansion in the diabetic condition. The data indicate that BMP4/Smad1 signaling is a critical cascade for the progression of mesangial expansion and that blocking this signal could be a novel therapeutic strategy for diabetic nephropathy.
Eriko Shibata, Kojiro Nagai, Risa Takeuchi, Yasuhiro Noda, Tomomi Makino, Yusuke Chikata, Michael Hann, Sakiya Yoshimoto, Hiroyuki Ono, Sayo Ueda, Masanori Tamaki, Taichi Murakami, Motokazu Matsuura, Hideharu Abe and Toshio Doi : Re-evaluation of Pre-pump Arterial Pressure to Avoid Inadequate Dialysis and Hemolysis: Importance of Prepump Arterial Pressure Monitoring in Hemodialysis Patients., Artificial Organs, Vol.39, No.7, 627-634, 2015.
(要約)
Prepump arterial pressure (PreAP) is monitored to avoid generating excessive negative pressure. The National Kidney Foundation K/DOQI clinical practice guidelines for vascular access recommend that PreAP should not fall below -250 mm Hg because excessive negative PreAP can lead to a decrease in the delivery of blood flow, inadequate dialysis, and hemolysis. Nonetheless, these recommendations are consistently disregarded in clinical practice and pressure sensors are often removed from the dialysis circuit. Thus far, delivered blood flow has been reported to decrease at values more negative than -150 mm Hg of PreAP. These values have been analyzed by an ultrasonic flowmeter and not directly measured. Furthermore, no known group has evaluated whether PreAP-induced hemolysis occurs at a particular threshold. Therefore, the aim of this study was to clarify the importance of PreAP in the prediction of inadequate dialysis and hemolysis. By using different diameter needles, human blood samples from healthy volunteers were circulated in a closed dialysis circuit. The relationship between PreAP and delivered blood flow or PreAP and hemolysis was investigated. We also investigated the optimal value for PreAP using several empirical monitoring methods, such as a pressure pillow. Our investigation indicated that PreAP is a critical factor in the determination of delivered blood flow and hemolysis, both of which occured at pressure values more negative than -150 mm Hg. With the exception of direct pressure monitoring, commonly used monitoring methods for PreAP were determined to be ineffective. We propose that the use of a vacuum monitor would permit regular measurement of PreAP.
Kazuhiro Yoshikawa, Hideharu Abe, Tatsuya Tominaga, Masayuki Nakamura, Seiji Kishi, Motokazu Matsuura, Kojiro Nagai, Kenji Tsuchida, Jun Minakuchi and Toshio Doi : Polymorphism in the human matrix Gla protein gene is associated with the progression of vascular calcification in maintenance hemodialysis patients, Clinical and Experimental Nephrology, Vol.17, No.6, 882-889, 2013.
(要約)
Matrix Gla protein (MGP) is one of the important proteins inhibiting vascular calcification (VC). Single nucleotide polymorphisms (SNPs) located in the promoter and coding regions of the MGP gene affect the transcriptional activity. In this study, we investigated the relationship between the SNPs and progression of VC in patients undergoing maintenance hemodialysis (MHD). This was a retrospective, longitudinal cohort study of 134 MHD patients whose VC could be followed by multi-detector computed tomography (MDCT) examinations. MGP-SNPs (T-138C, rs1800802 and G-7A, rs1800801) were determined. The progression speed of VC was examined by plotting the abdominal aortic calcium volume scores. The progression speed of VC of patients with the CC genotype of T-138C was significantly slower than that of patients with the CT or TT genotype. Multiple regression analysis showed that CT/TT genotype, greater age at the beginning of MHD, male sex, high levels of calcium × phosphate, low levels of high-density lipoprotein cholesterol, high levels of low-density lipoprotein cholesterol, low levels of ferritin and non-use of angiotensin II receptor blockers were significantly associated with progression of VC. The MGP-138CC genotype may be associated with slower progression of VC in MHD patients. The genotype of the MGP gene will be a genomic biomarker that is predictive of VC progression.
Kojiro Nagai, Masashi Miyoshi, Takei Kake, Naoshi Fukushima, Motokazu Matsuura, Eriko Shibata, Satoshi Yamada, Kazuhiro Yoshikawa, Hiro-omi Kanayama, Tomoya Fukawa, Kunihisa Yamaguchi, Hirofumi Izaki, Akira Mima, Naoko Abe, Toshikazu Araoka, Taichi Murakami, Fumi Kishi, Seiji Kishi, Tatsuya Tominaga, Tatsumi Moriya, Hideharu Abe and Toshio Doi : Dual Involvement of Growth Arrest-specific Gene 6 in the Early Phase of Human IgA Nephropathy, PLoS ONE, Vol.8, No.6, e66759, 2013.
(要約)
Gas6 is a growth factor that causes proliferation of mesangial cells in the development of glomerulonephritis. Gas6 can bind to three kinds of receptors; Axl, Dtk, and Mer. However, their expression and functions are not entirely clear in the different glomerular cell types. Meanwhile, representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN). The aim of this study is to clarify Gas6 involvement in the progression of IgAN. Expression of Gas6/Axl/Dtk was examined in 31 biopsy proven IgAN cases. We compared the expression levels with histological severity or clinical data. Moreover, we investigated the expression of Gas6 and its receptors in cultured podocytes. In 28 of 31 cases, Gas6 was upregulated mainly in podocytes. In the other 3 cases, Gas6 expression was induced in endothelial and mesangial cells, which was similar to animal nephritis models. Among 28 podocyte type cases, the expression level of Gas6 correlated with the mesangial hypercellularity score of IgAN Oxford classification and urine protein excretion. It also inversely correlated with p27 expression in glomeruli. As for the receptors, Axl was mainly expressed in endothelial and mesangial cells, while Dtk was expressed in podocytes. In vitro, Dtk was expressed in cultured murine podocytes, and the expression of p27 was decreased by Gas6 stimulation. Gas6 was uniquely upregulated in either endothelial/mesangial cells or podocytes in IgAN. The expression pattern can be used as a marker to classify IgAN. Gas6 has a possibility to be involved in not only mesangial proliferation via Axl, but also podocyte injury via Dtk in IgAN.
Seiji Kishi, Satoshi Yamada, Fumi Kishi, Eriko Shibata, Motokazu Matsuura, Kojiro Nagai, Akira Mima, Hideharu Abe and Toshio Doi : Acute Glomerulonephritis in an Immunocompetent Elderly Woman after Contact with a Child who Had Been Diagnosed as Erythema Infectiosum., Internal Medicine, Vol.51, No.16, 2197-2201, 2012.
(要約)
The prevalence of postinfectious glomerulonephritis has decreased in most developed countries. We report the case of a previously healthy, immunocompetent 65-year-old woman who developed acute glomerulonephritis associated with human parvovirus B19 infection. She was referred by her primary care physician for suspected congestive heart failure but she had an elevated creatinine level and an abnormal urinalysis. Renal biopsy showed diffuse endocapillary proliferative glomerulonephritis. After biopsy, we learned that she had been in frequent contact with her grandson who had been diagnosed with erythema infectiosum. Her human parvovirus B19 serum IgM titer was elevated at 3.50, indicating current infection.
Masanori Shibata, Kojiro Nagai, Toshio Doi, Hideo Tawada and Shinkichi Taniguchi : Blood Color Is Influenced by Inflammation and Independently Predicts Survival in Hemodialysis Patients: Quantitative Evaluation of Blood Color., Artificial Organs, Vol.36, No.11, 992-998, 2012.
(要約)
Blood color of dialysis patients can be seen routinely. Darkened blood color is often observed in critically ill patients generally because of decreased oxygen saturation, but little is known about the other factors responsible for the color intensity. In addition, quantitative blood color examination has not been performed yet. Therefore, no one has evaluated the predictive power of blood color. The aim of this study was to evaluate if blood color darkness reflects some medical problems and is associated with survival disadvantage. Study design is a prospective cohort study. One hundred sixty-seven patients were enrolled in this study. Quantification of blood color was done using a reflected light colorimeter. Demographic and clinical data were collected to find out the factors that can be related to blood color. Follow-ups were performed for 2 years to analyze the risk factors for their survival. Regression analysis showed that C-reactive protein and white blood cell count were negatively correlated with blood color. In addition, blood color was positively correlated with mean corpuscular hemoglobin concentration and serum sodium concentration as well as blood oxygen saturation. During a follow-up, 34 (20.4%) patients died. Cox regression analysis revealed that darkened blood color was an independent significant risk factor of mortality in hemodialysis patients as well as low albumin and low Kt/V. These results suggest that inflammation independently affects blood color and quantification of blood color is useful to estimate prognosis in patients undergoing hemodialysis. It is possible that early detection of blood color worsening can improve patients' survival.
Kazuo Torikoshi, Hideharu Abe, Takeshi Matsubara, Takahiro Hirano, Takayuki Ohshima, Taichi Murakami, Makoto Araki, Akira Mima, Noriyuki Iehara, Atsushi Fukatsu, Toru Kita, Hidenori Arai and Toshio Doi : Protein Inhibitor of Activated STAT, PIASy Regulates α-Smooth Muscle Actin Expression by Interacting with E12 in Mesangial Cells., PLoS ONE, Vol.7, No.7, e41186, 2012.
(要約)
Phenotypic transformation of mesangial cells (MCs) is implicated in the development of glomerular disease; however, the mechanisms underlying their altered genetic program is still unclear. α-smooth muscle actin (α-SMA) is known to be a crucial marker for phenotypic transformation of MCs. Recently, E-boxes and the class I basic helix-loop-helix proteins, such as E12 have been shown to regulateα-SMA expression. Therefore, we tried to identify a novel E12 binding protein in MCs and to examine its role in glomerulonephritis. We found that PIASy, one of the protein inhibitors of activated STAT family protein, interacted with E12 by yeast two-hybrid screens and coimmunopreciptation assays. Overexpression of E12 significantly enhanced theα-SMA promoter activity, and the increase was blocked by co-transfection of PIASy, but not by a PIASy RING mutant. In vivo sumoylation assays revealed that PIASy was a SUMO E3 ligase for E12. Furthermore, transforming growth factor-β (TGF-β) treatment induced expression of both PIASy and E12, consistent with α-SMA expression. Moreover, reduced expression of PIASy protein by siRNA specific for PIASy resulted in increased TGF-β-mediated α-SMA expression. In vivo, PIASy and E12 were dramatically upregulated along with α-SMA and TGF-β in the proliferative phase of Thy1 glomerulonephritis. Furthermore, an association between PIASy and E12 proteins was observed at day 6 by IP-western blotting, but not at day 0. These results suggest that TGF-β up-regulates PIASy expression in MCs to down-regulateα-SMA gene transcription by the interaction with E12.
(キーワード)
Actins / Animals / Blotting, Western / COS Cells / Cell Line / Cell Proliferation / Humans / 免疫組織化学 (immunohistochemistry) / Immunoprecipitation / Male / Mesangial Cells / Protein Binding / Protein Inhibitors of Activated STAT / RNA Interference / Rats / Rats, Inbred WKY / Reverse Transcriptase Polymerase Chain Reaction / Transcription Factor 3 / Two-Hybrid System Techniques
Seiji Kishi, K Kanaji, Toshio Doi and T Matsumura : A case of traumatic intracranial vertebral artery injury presenting with life-threatening symptoms., International Medical Case Reports Journal, Vol.5, No.1, 23-28, 2012.
Hideharu Abe, Tatsuya Tominaga, Takeshi Matsubara, Naoko Abe, Seiji Kishi, Kojiro Nagai, Taichi Murakami, Toshikazu Araoka and Toshio Doi : Scleraxis modulates bone morphogenetic protein 4 (BMP4)-Smad1 protein-smooth muscle -actin (SMA) signal transduction in diabetic nephropathy., The Journal of Biological Chemistry, Vol.287, No.24, 20430-20442, 2012.
(要約)
Activation of mesangial cells (MCs), which is characterized by induction of smooth muscle -actin (SMA) expression, contributes to a key event in various renal diseases; however, the mechanisms controlling MC differentiation are still largely undefined. Activated Smad1 induced SMA in a dose-dependent manner in MCs. As a direct regulating molecule for SMA, we identified and characterized scleraxis (Scx) as a new phenotype modulator in advanced glycation end product (AGE)-exposed MCs. Scx physically associated with E12 and bound the E-box in the promoter of SMA and negatively regulated the AGE-induced SMA expression. Scx induced expression and secretion of bone morphogenetic protein 4 (BMP4), thereby controlling the Smad1 activation in AGE-treated MCs. In diabetic mice, Scx was concomitantly expressed with SMA in the glomeruli. Inhibitor of differentiation 1 (Id1) was further induced by extended treatment with AGE, thereby dislodging Scx from the SMA promoter. These data suggest that Scx and Id1 are involved in the BMP4-Smad1-SMA signal transduction pathway besides the TGF1-Smad1-SMA signaling pathway and modulate phenotypic changes in MCs in diabetic nephropathy.
Seiji Kishi, Hideharu Abe, Haruhiko Akiyama, Tatsuya Tominaga, Taichi Murakami, Akira Mima, Kojiro Nagai, Fumi Kishi, Motokazu Matsuura, Takeshi Matsubara, Noriyuki Iehara, Otoya Ueda, Naoshi Fukushima, Kou-Ichi Jishage and Toshio Doi : SOX9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy., The Journal of Biological Chemistry, Vol.286, No.37, 32162-32169, 2011.
(要約)
Diabetic nephropathy (DN) is the most important chronic kidney disease. We previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix in DN. Phenotypic change in mesangial cells (MCs) is a key pathologic event in the progression of DN. The aim of this study is to investigate a novel mechanism underlying chondrogenic phenotypic change in MCs that results in the development of DN. MCs showed chondrogenic potential in a micromass culture, and BMP4 induced the expression of chondrocyte markers (SRY-related HMG Box 9 (SOX9) and type II collagen (COL2)). Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of BMP4, hypoxia-inducible factor-1 (HIF-1), and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of proteoglycans and COL2 in MCs. Furthermore, forced expression of Smad1 induced chondrocyte markers as well. Dorsomorphin inhibited these inductions. Glomerular expressions of HIF-1, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. These positive stainings were observed in mesangial sclerotic lesions. SOX9 was partially colocalized with HIF-1 and BMP4 in diabetic glomeruli. BMP4 knock-in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. Here we demonstrate that HIF-1 and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN.
(キーワード)
Animals / Antigens, Differentiation / Bone Morphogenetic Protein 4 / Cell Line / Cell Transdifferentiation / Chondrocytes / Collagen Type II / Diabetic Nephropathies / Gene Expression Regulation / Glomerular Mesangium / Glycosylation End Products, Advanced / Hypoxia-Inducible Factor 1, alpha Subunit / Mice / Mice, Transgenic / SOX9 Transcription Factor / Smad1 Protein
Akira Mima, Fumihiko Shiota, Takeshi Matsubara, Noriyuki Iehara, Taro Akagi, Hideharu Abe, Kojiro Nagai, Motokazu Matsuura, Taichi Murakami, Seiji Kishi, Toshikazu Araoka, Fumi Kishi, Naoki Kondo, Reiko Shigeta, Kazuhiro Yoshikawa, Toru Kita, Toshio Doi and Atsushi Fukatsu : An autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with intestinal bleeding in chronic renal failure., Renal Failure, Vol.33, No.6, 622-625, 2011.
(要約)
A 50-year-old man who underwent hemodialysis (HD) at local outpatient HD center due to end-stage renal disease (ESRD) was transferred to our hospital because of pneumonia. He had severe emaciation and past history of congestive heart failure. Presenting symptoms almost consistently involved difficulty in hearing and recurrent attacks of migraine-like headaches. He was diagnosed with dilated cardiomyopathy, showing diastolic mechanical dyssynchrony by tissue Doppler echocardiography. On the day of death, he had hematemesis and hemorrhagic shock. Autopsy revealed perforation of duodenum, and genetic analysis using mitochondrial DNA from cardiac muscle and iliopsoas muscle revealed a 3243A > G mutation in the mitochondrial tRNA(Leu(UUR)) gene, which is related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Multiple organ failure due to the mutation of mitochondrial DNA with gastrointestinal bleeding is not a common.
Tatsuya Tominaga, Hideharu Abe, Otoya Ueda, Chisato Goto, Kunihiko Nakahara, Taichi Murakami, Takeshi Matsubara, Akira Mima, Kojiro Nagai, Toshikazu Araoka, Seiji Kishi, Naoshi Fukushima, Kou-ichi Jishage and Toshio Doi : Activation of bone morphogenetic protein 4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy., The Journal of Biological Chemistry, Vol.286, No.22, 20109-20116, 2011.
(要約)
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease. We have previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix (ECM) proteins in DN. However, little is known about the regulatory mechanisms that induce and activate Smad1. Here, bone morphogenetic protein 4 (Bmp4) was found to up-regulate the expression of Smad1 in mesangial cells and subsequently to phosphorylate Smad1 downstream of the advanced glycation end product-receptor for advanced glycation end product signaling pathway. Moreover, Bmp4 utilized Alk3 and affected the activation of Smad1 and Col4 expressions in mesangial cells. In the diabetic mouse, Bmp4 was remarkably activated in the glomeruli, and the mesangial area was expanded. To elucidate the direct function of Bmp4 action in the kidneys, we generated transgenic mice inducible for the expression of Bmp4. Tamoxifen treatment dramatically induced the expression of Bmp4, especially in the glomeruli of the mice. Notably, in the nondiabetic condition, the mice exhibited not only an expansion of the mesangial area and thickening of the basement membrane but also remarkable albuminuria, which are consistent with the distinct glomerular injuries in DN. ECM protein overexpression and activation of Smad1 in the glomeruli were also observed in the mice. The mesangial expansion in the mice was significantly correlated with albuminuria. Furthermore, the heterozygous Bmp4 knock-out mice inhibited the glomerular injuries compared with wild type mice in diabetic conditions. Here, we show that BMP4 may act as an upstream regulatory molecule for the process of ECM accumulation in DN and thereby reveals a new aspect of the molecular mechanisms involved in DN.
(キーワード)
Albuminuria / Animals / Bone Morphogenetic Protein 4 / Diabetic Nephropathies / 細胞外マトリックス (extracellular matrix) / Glomerulosclerosis, Focal Segmental / Glycosylation End Products, Advanced / Mesangial Cells / Mice / ノックアウトマウス (knockout mice) / Smad1 Protein / Up-Regulation
Hideharu Abe, Takeshi Matsubara, Hidenori Arai and Toshio Doi : Role of Smad1 in diabetic nephropathy: Molecular mechanisms and implications as a diagnostic marker., Histology and Histopathology, Vol.26, No.4, 531-541, 2011.
(要約)
Diabetic nephropathy (DN) is the leading cause of chronic kidney failure. Moreover, DN is associated with elevated cardiovascular morbidity and mortality. DN is characterized by progressive expansion of the mesangial matrix and thickening of the glomerular basement membrane, resulting in the obliteration of glomerular capillaries. Advanced glycation endproducts (AGEs) produced as the result of hyperglycemia are known to stimulate the production of extracellular matrix (ECM) proteins, resulting in glomerulosclerosis. Exposure of cultured mesangial cells to AGEs results in a receptor-mediated upregulation of mRNA and protein secretion of type IV collagen (Col4), which is a major component of ECM. Here we review recent novel insights into the pathogenesis and diagnosis of DN, with a special emphasis on the emerging concept that diabetic glomerulosclerosis can result from activation of the signaling cascade leading to irreversible ECM overproduction. Finally, we describe signaling pathways involved in the initial change of DN and how these pathways can be manipulated for therapeutic benefit.
(キーワード)
Animals / Biological Markers / Cells, Cultured / Collagen Type IV / Diabetic Nephropathies / Glomerular Mesangium / Glycosylation End Products, Advanced / Humans / RNA, Messenger / Signal Transduction / Smad1 Protein / Up-Regulation
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21360446
Akira Mima, Hideharu Abe, Kojiro Nagai, Hidenori Arai, Takeshi Matsubara, Makoto Araki, Kazuo Torikoshi, Tatsuya Tominaga, Noriyuki Iehara, Atsushi Fukatsu, Toru Kita and Toshio Doi : Activation of Src mediates PDGF-induced Smad1 phosphorylation and contributes to the progression of glomerulosclerosis in glomerulonephritis., PLoS ONE, Vol.6, No.3, e17929, 2011.
(要約)
Platelet-derived growth factor (PDGF) plays critical roles in mesangial cell (MC) proliferation in mesangial proliferative glomerulonephritis. We showed previously that Smad1 contributes to PDGF-dependent proliferation of MCs, but the mechanism by which Smad1 is activated by PDGF is not precisely known. Here we examined the role of c-Src tyrosine kinase in the proliferative change of MCs. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, MC proliferation and type IV collagen (Col4) expression peaked on day 6. Immunohistochemical staining for the expression of phospho-Src (pSrc), phospho-Smad1 (pSmad1), Col4, and smooth muscle -actin (SMA) revealed that the activation of c-Src and Smad1 signals in glomeruli peaked on day 6, consistent with the peak of mesangial proliferation. When treated with PP2, a Src inhibitor, both mesangial proliferation and sclerosis were significantly reduced. PP2 administration also significantly reduced pSmad1, Col4, and SMA expression. PDGF induced Col4 synthesis in association with increased expression of pSrc and pSmad1 in cultured MCs. In addition, PP2 reduced Col4 synthesis along with decreased pSrc and pSmad1 protein expression in vitro. Moreover, the addition of siRNA against c-Src significantly reduced the phosphorylation of Smad1 and the overproduction of Col4. These results provide new evidence that the activation of Src/Smad1 signaling pathway plays a key role in the development of glomerulosclerosis in experimental glomerulonephritis.
Arteriosclerotic renal artery stenosis is one of the increasingly common diseases that affects many aged patients. There are various non-invasive methods to diagnose renal artery stenosis, such as contrast enhanced CT or MRI. However, these methods are not appropriate for patients with renal dysfunction. Ultrasound sonography is becoming one of the promising methods to diagnose artery stenosis because of photographic improvements. In this case, a 72-year-old woman was hospitalized 7 months after nephrectomy because of severe hypertension, heart failure and kidney dysfunction. The heart failure was quite uncontrollable in spite of massive administration of diuretics, and finally, hemodialysis was started to control her volume status. In consideration of her past history and abdominal bruit, we evaluated the renal artery stenosis by ultrasound sonography and confirmed the diagnosis by renal angiography. To improve hypertension control, we performed renal artery stenting, which resulted in an impressive improvement of her blood pressure and renal function. We recognized the importance of careful causal evaluation of renal dysfunction, even though it is difficult to apply invasive therapy to patients after nephrectomy.
Taichi Murakami, Hideharu Abe, Kojiro Nagai, Tatsuya Tominaga, Norimichi Takamatsu, Toshikazu Araoka, Seiji Kishi, Toshikazu Takahashi, Akira Mima, Yoshimi Takai, Jeffrey B. Kopp and Toshio Doi : Trophoblast glycoprotein: possible candidate mediating podocyte injuries in glomerulonephritis., American Journal of Nephrology, Vol.32, No.6, 505-521, 2010.
(要約)
trophoblast glycoprotein (Tpbg), a 72-kDa transmembrane glycoprotein, is known to regulate the phenotypes of epithelial cells by modifying actin organization and cell motility. Recently, a microarray study showed that Tpbg is upregulated in Thy1 glomerulonephritis (Thy1 GN). We hypothesized that Tpbg regulates cytoskeletal rearrangement and modulates phenotypic alteration in podocytes under pathological conditions.
Toshikazu Araoka, Hiroya Takeoka, Keisuke Nishioka, Masaki Ikeda, Makiko Kondo, Azusa Hoshina, Seiji Kishi, Makoto Araki, Rokuro Mimura, Taichi Murakami, Akira Mima, Kojiro Nagai, Hideharu Abe and Toshio Doi : Successful management of refractory pleural effusion due to systemic immunoglobulin light chain amyloidosis by vincristine adriamycin dexamethasone chemotherapy: a case report., Journal of Medical Case Reports, Vol.4, 322, 2010.
Toshikazu Araoka, Hideharu Abe, Tatsuya Tominaga, Akira Mima, Takeshi Matsubara, Taichi Murakami, Seiji Kishi, Kojiro Nagai and Toshio Doi : Transcription factor 7-like 2 (TCF7L2) regulates activin receptor-like kinase 1 (ALK1)/Smad1 pathway for development of diabetic nephropathy., Molecules and Cells, Vol.30, No.3, 209-218, 2010.
(要約)
Smad1 has previously been shown to play a key role in the development of diabetic nephropathy (DN), by increasing synthesis of extracellular matrix. However, the regulatory mechanism of Smad1 in DN is still unclear. This study aims to elucidate molecular interactions between activin receptor-like kinase 1 (ALK1)/Smad1 signaling pathway and transcription factor 7-like 2 (TCF7L2) in the progression of DN in vitro and in vivo. The expressions of TCF7L2 and ALK1 were induced by advanced glycation end products (AGEs) in parallel with Smad1, phosphorylated Smad1 (pSmad1), and alpha-smooth muscle actin (-SMA) through TGF-1 in cultured mesangial cells. Constitutively active ALK1 increased pSmad1 and -SMA expressions. The binding of TCF7L2 to ALK1 promoter was confirmed by chromatin immunoprecipitation assay. Furthermore, TCF7L2 induced promoter activity of ALK1. AGEs and TGF-1 induced a marked increase in TCF7L2 expression in parallel with ALK1. Overexpression of TCF7L2 increased the expressions of ALK1 and Smad1. Inversely, TCF7L2 knockdown by siRNA suppressed -SMA expression as well as ALK1 and Smad1. The iNOS transgenic mice (iNOS-Tgm), which developed diabetic glomerulosclerosis resembling human diabetic nephropathy, exhibited markedly increased expressions of ALK1, TCF7L2, Smad1, pSmad1, and -SMA in glomeruli in association with mesangial matrix expansion. These results provide a new evidence that the TCF7L2/ALK1/Smad1 pathway plays a key role in the development of DN.
(キーワード)
Activin Receptors, Type II / Animals / Cells, Cultured / Diabetic Nephropathies / Disease Progression / Glomerular Mesangium / Humans / Mesangial Cells / Mice / Mice, Transgenic / Nitric Oxide Synthase Type II / Protein Binding / RNA, Small Interfering / シグナル伝達 (signal transduction) / Smad1 Protein / Transcription Factor 7-Like 2 Protein / Transcriptional Activation / Transgenes
Toshikazu Araoka, Hiroya Takeoka, Hideharu Abe, Seiji Kishi, Makoto Araki, Keisuke Nishioka, Masaki Ikeda, Tetsuro Mazaki, Shiori Ikemura, Makiko Kondo, Azusa Hoshina, Kojiro Nagai, Akira Mima, Taichi Murakami, Rokuro Mimura, Kazumasa Oka, Takao Saito and Toshio Doi : Early diagnosis and treatment may prevent the development of complications in an adult patient with glycogen storage disease type Ia., Internal Medicine, Vol.49, No.16, 1787-1792, 2010.
(要約)
Type Iota(a) glycogen storage disease (GSD Iota(a)) is caused by the deficiency of glucose-6-phosphatase activity, which results in metabolic disorder and organ failure, including renal failure. GSD Iota(a) patients are generally diagnosed at a median age of 6 months. However, we report a 20-year-old Japanese female with newly diagnosed GSD Iota(a) . The renal disorder of GSD Iota(a) is considered to be produced by glomerular hyperfiltration, TGF-beta expression which is induced by renin-angiotensin-aldosterone system (RAS) and uric acid, and the increase in both small dense LDL and modified LDL which is characteristic of GSD Iota(a) as well as hypertriglyceridemia. With the administration of intensive therapies, including angiotensin type 1-receptor blocker and some lipid lowering drugs, along with traditional dietary therapy, daily proteinuria of the patient improved from 2.1 g to 0.78 g. Although the patients of GSD Iota(a) should receive an early and accurate diagnosis and effective therapies before the age of 1 year, the combination of traditional dietary therapies and intensive therapies may have therapeutic potential for the complications of adult patients. In this report, we describe the management of renal disease and the characteristic features of this metabolic disorder.
(キーワード)
Early Diagnosis / Female / Glycogen Storage Disease Type I / Humans / Kidney Diseases / Kidney Glomerulus / Treatment Outcome / Young Adult
A Mima, N Iehara, T Matsubara, S Yamamoto, Hideharu Abe, Kojiro Nagai, M Matsuura, T Murakami, S Kishi, T Araoka, F Kishi, N Kondo, R Shigeta, K Yoshikawa, T Takahashi, T Kita, Toshio Doi and A Fukatsu : Successful treatment of membranoproliferative glomerulonephritis associated with hepatitis B and C virus simultaneous infection patient., Clinical Nephrology, Vol.73, No.2, 167-169, 2010.
Hidekazu Arai, Naomi Awane, Akira Mizuno, Makiko Fukaya, Masae Sakuma, Nagakatsu Harada, Akihiko Kawaura, Hironori Yamamoto, Hisami Okumura, Yutaka Taketani, Toshio Doi and Eiji Takeda : Increasing early insulin secretion compensate adequately for hepatic insulin resistance in CCl4-induced cirrhosis rats., The Journal of Medical Investigation : JMI, Vol.57, No.1-2, 54-61, 2010.
(要約)
A number of recent publications have reported an increased frequency prevalence of glucose intolerance with hyperinsulinemia in liver cirrhosis. The aim of this work was to detect, in CCl(4)-induced liver cirrhosis rat, the presence and starting point of muscle and liver insulin resistance. Eighteen rats received intraperitoneal injection of 2 ml of soybean oil containing of CCl(4) twice a week for 20 weeks. We executed standard oral glucose tolerance and clamp study to evaluate systemic insulin resistance. Hepatic glucose uptake was much lower in CCl(4) group than that in control group, but peripheral glucose uptake was not decreased in this study. In contrast, early-phase insulin secretion was enhanced in CCl(4) rat using oral glucose load during clamp methods. These data suggested that increased early insulin secretion compensate adequately for hepatic insulin resistance in rats. However there was a report that peripheral glucose uptake was decreased in the case of human liver cirrhosis, which was formed in the course of time. In a chronic condition, this may be associated with reduced insulin content and developed systemic insulin resistance in liver cirrhosis. Then a long term observation study will be required to examine the presence of muscle insulin resistance in liver cirrhosis.
Norimichi Takamatsu, Hideharu Abe, Tatsuya Tominaga, Kunihiko Nakahara, Yumi Ito, Yoko Okumoto, Jiyoong Kim, Masafumi Kitakaze and Toshio Doi : Risk factors for chronic kidney disease in Japan: a community-based study., BMC Nephrology, Vol.10, 34, 2009.
(要約)
Chronic kidney disease (CKD) is increasingly being recognized as a predictor for both end-stage renal disease and cardiovascular disease. The present study, conducted on individuals from a community in Arita, Japan, was designed to evaluate biomarkers that can be used to determine the associated factors for CKD.
(キーワード)
Adult / Aged / Aged, 80 and over / Cross-Sectional Studies / Female / Glomerular Filtration Rate / Humans / 日本 (Japan) / Kidney Failure, Chronic / Male / Middle Aged / Residence Characteristics / Risk Factors / Young Adult
Akira Mima, Masanao Toma, Takeshi Matsubara, Fumihiko Shiota, Noriyuki Iehara, Hideharu Abe, Kojiro Nagai, Toshikazu Takahashi, Motokazu Matsuura, Taichi Murakami, Seiji Kishi, Toshikazu Araoka, Fumi Kishi, Naoki Kondo, Reiko Shigeta, Kazuhiro Yoshikawa, Takeshi Kimura, Toru Kita, Toshio Doi and Atsushi Fukatsu : Angio-embolization of renal artery pseudoaneurysm after renal biopsy: a case report., Renal Failure, Vol.31, No.8, 753-755, 2009.
(要約)
Renal artery pseudoaneurysm is a rare clinical entity that has been reported after renal biopsy, percutaneous renal surgery, penetrating trauma, and rarely blunt renal trauma. We present the case of a 37-year-old man with ruptured renal artery pseudoaneurysm accompanied by massive gross hematuria, urinary clot retention, and bladder tamponade, which were the presenting signs seven hours after renal biopsy. Abdominal CT scan showed a large perinephric, intracapsular hematoma of left kidney. His angiogram revealed a left renal segmental artery pseudoaneurysm that measured 1 cm x 1 cm. He was successfully treated by selective embolization of the arterial branch supplying the pseudoaneurysm.
Toshio Doi, Akira Mima, Takeshi Matsubara, Tatsuya Tominaga, Hidenori Arai and Hideharu Abe : The current clinical problems for early phase of diabetic nephropathy and approach for pathogenesis of diabetic nephropathy., Diabetes Research and Clinical Practice, Vol.82, No.Suppl 1, S21-4, 2008.
(要約)
The important clinical problems of diabetic nephropathy are both proteinuria and decrease of renal function. Pathological analysis showed decrease of GFR was correlated to degree of mesangial expansion but not thickening of GBM nor the other findings in human type 1 diabetic nephropathy. From the perspective in renal dysfunction, mesangial matrix expansion was crucial for diabetic nephropathy. However, there was no difference of mesangial expansion between normal and microalbuminuria stage in type 1 and 2 diabetes mellitus (DM). On the other hand, microalbuminuria definitely shows a key related factor for cardiovascular events, but it does not indicate a clear interaction for glomerulosclerosis. We need to search a new clinical marker for renal injury. We have first shown that Smad1 is a transcription factor for alpha1 and 2 of type 4 collagen (Col4), which is a major component of glomerulosclerosis. We have also identified Smad1 is a critical responsible molecule for developing glomerulosclerosis in rat diabetic nephropathy. We have found the good correlation between glomerulosclerosis and urinary Smad1 but not between glomerulosclerosis and urine albumin. These data suggests that urine Smad1 is a promising clinical marker for underlying glomerular damages in early stage diabetic nephropathy. The study also implicates that angiotensin II (AngII)-Src-Smad1 signaling pathway has played a key role for development of diabetic nephropathy. These suggest that it is necessary to clarify the whole mechanism related to Smad1 to identify the pathogenesis of diabetic nephropathy.
Masamichi Kuwajima, Hiroaki Fujihara, Hiroyoshi Sei, Asako Umehara, Masako Sei, Tomi T. Tsuda, Akiko Sukeno, Tatsuya Okamoto, Akiko Inubushi, Yoichi Ueta, Toshio Doi and Hiroshi Kido : Reduced carnitine level causes death from hypoglycemia: possible involvement of suppression of hypothalamic orexin expression during weaning period., Endocrine Journal, Vol.54, No.6, 911-925, 2007.
(要約)
The mechanism of onset of hypoglycemia in patients with carnitine deficiency has yet to be determined. Using mice with systemic carnitine deficiency (JVS mice), we examined this mechanism, focusing on the weaning period (days 14-28 postpartum). For normal mice, the survival rate was 100%, and no hypoglycemia was observed at all. Gastric lactose began to decrease on day 17, and cellulose increased sharply in amount thereafter. For JVS mice, the survival rate was 77% on day 14 and 28% on day 28. From day 21 on, hypoglycemia was noted. Gastric lactose had disappeared almost completely by day 17, and cellulose was almost undetectable from days 14 to 28. Expression of orexin mRNA in the hypothalamus did not differ between JVS and normal mice on day 14, but was suppressed in JVS mice on days 21 and 28. When JVS mice were fed a carnitine-rich diet, suppression of expression of orexin mRNA in hypothalamus was eliminated, and on day 28 lactose and cellulose were detected in the stomach without hypoglycemia. In conclusion, the suppression of the expression of orexin in the hypothalamus during the weaning period may be involved in the marked anorexia in JVS mice, which eventually leads to death from hypoglycemia.
Kazusa Sato, Hidekazu Arai, Akira Mizuno, Makiko Fukaya, Tadatoshi Sato, Megumi Koganei, Hajime Sasaki, Hironori Yamamoto, Yutaka Taketani, Toshio Doi and Eiji Takeda : Dietary palatinose and oleic acid ameliorate disorders of glucose and lipid metabolism in zucker fatty rats., The Journal of Nutrition, Vol.137, No.8, 1908-1915, 2007.
(要約)
Excessive dietary intake of carbohydrates and fats has been linked to the development of obesity. However, the mechanism by which these dietary factors interact to bring about metabolic changes has not been elucidated. We examined the combined effects of different types of dietary carbohydrates and fats on the etiology of obesity and its complications in the Zucker fatty (fa/fa) rat, a model of obesity. Specifically, these rats were fed an isocaloric diet containing various combinations of carbohydrates [palatinose (P), an insulin-sparing sucrose analogue, and sucrose (S)] and fatty acids [oleic acid (O) and linoleic acid (L)]. After 8 wk, palatinose feeding (PO and PL) led to significant reductions in visceral fat mass, adipocyte cell size, hyperglycemia, and hyperlipidemia compared with sucrose feeding (SO and SL); pancreatic islet hypertrophy was also prevented by palatinose feeding. Linoleic-acid-fed rats (PL and SL) exhibited reduced insulin-immunoreactive staining of the pancreatic islets, enhanced macrophage infiltration in adipose tissue, and an elevated plasma tumor necrosis factor-alpha concentration when compared with oleic-acid-fed rats (PO and SO). Furthermore, sucrose and linoleic acid synergistically increased the expression of genes involved in hepatic gluconeogenesis and lipogenesis [sterol regulatory-element binding protein (SREBP)-1c and SREBP-2]. In conclusion, a diet containing palatinose and oleic acid may prevent diet-induced metabolic abnormalities. The combination of palatinose and oleic acid holds promise for a new approach to preventing and treating obesity and its complications.
Akira Mizuno, Hidekazu Arai, Makiko Fukaya, Mitsuyo Sato, Hisami Okumura, Eiji Takeda and Toshio Doi : Early-phase insulin secretion is distributed in obese subjects with glucose intolerance., Metabolism: Clinical and Experimental, Vol.56, No.6, 856-862, 2007.
(要約)
The loss of early-phase insulin secretion is a characteristic feature of type 2 diabetes mellitus. The aim of this study is to examine when impairment of early-phase insulin secretion occurs and whether it can be related to increase in insulin resistance caused by obesity. We developed an analytical method to qualify the early-phase insulin secretion; that is, we measured C-peptide immunoreactivity (CPR) response to a selective increase in blood glucose level in portal vein during oral glucose load under a euglycemic hyperinsulinemic clamp (clamp-OGL). Glucose infusion rate, hepatic glucose uptake, and CPR response during clamp-OGL were measured in 30 subjects with diabetes who were divided into 3 groups based on body mass index, 13 obese subjects with normal glucose tolerance (O-NGT), 10 obese subjects with impaired glucose tolerance (O-IGT), and 15 healthy subjects. Significant increase in CPR levels at 10 minutes in clamp-OGL compared with those at steady state was observed in healthy subjects and in O-NGT; however, those were small or absent in diabetic patients and in O-IGT. The incremental ratio of CPR was not correlated to the makers of insulin resistance. The early-phase insulin secretion is well maintained in O-NGT; however, early-phase insulin secretion has already been disturbed in obese subjects with glucose intolerance.
Makiko Fukaya, Akira Mizuno, Hidekazu Arai, Kazusa Muto, Takashi Uebanso, Kaoru Matuo, Hironori Yamamoto, Yutaka Taketani, Toshio Doi and Eiji Takeda : Mechanism of rapid-phase insulin response to elevation of portal glucose concentration., American Journal of Physiology, Endocrinology and Metabolism, Vol.293, No.2, E515-22, 2007.
(要約)
The hepatoportal region is important for glucose sensing; however, the relationship between the hepatoportal glucose-sensing system and the postprandial rapid phase of the insulin response has been unclear. We examined whether a rapid-phase insulin response to low amounts of intraportal glucose infusion would occur, compared that with the response to intrajugular glucose infusion in conscious rats, and assessed whether this sensing system was associated with autonomic nerve activity. The increases in plasma glucose concentration did not differ between the two infusions at 3 min, but the rapid-phase insulin response was detected only in the intraportal infusion. A sharp and rapid insulin response was observed at 3 min after intraportal infusion of a small amount of glucose but not after intrajugular infusion. Furthermore, this insulin response was also induced by intraportal fructose infusion but not by nonmetabolizable sugars. The rapid-phase insulin response at 3 min during intraportal infusion did not differ between rats that had undergone hepatic vagotomy or chemical sympathectomy with 6-hydroxydopamine compared with control rats, but this response disappeared in rats that had undergone chemical vagotomy with atropine. We conclude that the elevation of glucose concentration in the hepatoportal region induced afferent signals from undetectable sensors and that these signals stimulate pancreas to induce the rapid-phase insulin response via cholinergic nerve action.
Kaoru Matsuo, Hidekazu Arai, Kazusa Muto, Makiko Fukaya, Tadashi Sato, Akira Mizuno, Masae Sakuma, Hisami Okumura, Hajime Sasaki, Hironori Yamamoto, Yutaka Taketani, Toshio Doi and Eiji Takeda : The anti-obesity effect of the palatinose-based formula Inslow is likely due to an increase in the hepatic PPAR-α and adipocyte PPAR-γ gene expressions., Journal of Clinical Biochemistry and Nutrition, Vol.40, No.3, 234-241, 2007.
(要約)
Abdominal obesity is a principal risk factor in the development of metabolic syndrome. Previously, we showed that a palatinose-based liquid formula, Inslow/MHN-01, suppressed postprandial plasma glucose level and reduced visceral fat accumulation better than the standard formula (SF). To elucidate the mechanism of Inslow-mediated anti-obesity effect, expression levels of genes involved in the glucose and lipid metabolism were compared in Inslow- and SF-fed rats. Both fasting plasma insulin level and average islet sizes were reduced in the Inslow group. We also found less abdominal fat accumulation and reduced hepatic triacylglycerol content in the Inslow group. Expression of the beta-oxidation enzymes and uncoupling potein-2 (UCP-2) mRNAs in the liver of the Inslow group were higher than the SF group, which was due to a concomitant higher expression of the peroxisome proliferator-activated receptor (PPAR)-alpha mRNA in the former. Furthermore, expression of the UCP-2 and adiponectin mRNAs in the epididymal fat were higher in the Inslow group than the SF group, and were stimulated by a concomitant increase of the PPAR-gamma gene expression in the former. These results strongly suggested that the anti-obesity effect of Inslow was due to an increase in the hepatic PPAR-alpha and adipocyte PPAR-gamma gene expressions.
Hidekazu Arai, Akira Mizuno, Masae Sakuma, Makiko Fukaya, Kaoru Matsuo, Kazusa Muto, Hajime Sasaki, Motoi Matsuura, Hisami Okumura, Hironori Yamamoto, Yutaka Taketani, Toshio Doi and Eiji Takeda : Effects of a palatinose-based liquid diet (Inslow) on glycemic control and the second-meal effect in healthy men., Metabolism: Clinical and Experimental, Vol.56, No.1, 115-121, 2007.
(要約)
Postprandial hyperglycemia induces prolonged hyperinsulinemia, which is a risk factor for type 2 diabetes mellitus. Foods with a low glycemic index blunt the rapid rise in postprandial plasma glucose and insulin levels. We herein investigated the effects of a novel, palatinose-based liquid diet (Inslow, Meiji Dairy Products, Tokyo, Japan) on postprandial plasma glucose and insulin levels and on the rate of substrate oxidation in 7 healthy men. Furthermore, to examine the effects of Inslow on the second-meal effect, we quantified our subjects' postprandial plasma glucose, insulin, and free fatty acid levels for up to 7 hours after they ingested a breakfast containing Inslow or control formula, followed by a standard lunch 5 hours later. Our results showed that peak plasma glucose and insulin levels 30 minutes after Inslow loading were lower than after control formula loading. Postprandial fat oxidation rates in the Inslow group were higher than in the control formula group (P < .05). In the second-meal effect study, plasma glucose and insulin levels after lunch in the Inslow group were lower than in the control formula group (P < .01), although the peak levels in these groups were not different. The free fatty acid concentration in the Inslow group immediately before lunch was significantly lower than in the control formula group (P < .05). In conclusion, consumption of Inslow at breakfast appears to improve patient glycemic control by reducing their postprandial plasma glucose and insulin levels after lunch (second-meal effect).
(キーワード)
Adult / Blood Glucose / Cross-Over Studies / Energy Metabolism / Fatty Acids, Nonesterified / Humans / Insulin / Isomaltose / Male / Oxidation-Reduction / Postprandial Period
Takeshi Matsubara, Hideharu Abe, Hidenori Arai, Kojiro Nagai, Akira Mima, Hiroshi Kanamori, Eriko Sumi, Toshikazu Takahashi, Motokazu Matsuura, Noriyuki Iehara, Atsushi Fukatsu, Toru Kita and Toshio Doi : Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy., Laboratory Investigation; a Journal of Technical Methods and Pathology, Vol.86, No.4, 357-368, 2006.
(要約)
Diabetic nephropathy is the leading cause of end-stage renal disease, and glomerular mesangial matrix expansion is the hallmark in diabetic nephropathy. However, the precise mechanism for the development of mesangial matrix expansion has remained unknown. The key component involved in mesangial matrix expansion is type IV collagen (Col4). Recently, we have reported that Smad1 transcriptionally regulates expression of Col4 under diabetic conditions in vitro. Here we show that this direct regulator of Col4 also plays a crucial role for mesangial matrix expansion in vivo. Streptozotocin-induced diabetic rats are the model of incipient diabetic nephropathy, and showed various levels of mesangial matrix expansion at 24 weeks. The glomerular expression of Smad1 was significantly increased in diabetic rats with more mesangial matrix expansion by Western blot and immunohistochemical analysis. Furthermore, the glomerular expression of Smad1 was closely correlated with the glomerular expression of Col4 and smooth muscle alpha actin (alpha-SMA), while albuminuria or glomerular filtration rate was not correlated with mesangial matrix expansion. We also found that urinary excretion of Smad1 was closely associated with the severity of mesangial matrix expansion. In cultured mesangial cells expression of Smad1 upregulated the transcriptional activity of key molecules in mesangial matrix expansion, such as Col4 and alpha-SMA. These data indicate the critical involvement of Smad1 in mesangial matrix expansion in the early phase of diabetic nephropathy. Our data imply that urinary Smad1 might be a representative diagnostic marker for mesangial matrix expansion in diabetic nephropathy.
Hidekazu Arai, Akira Mizuno, Kaoru Matsuo, Makiko Fukaya, Hajime Sasaki, Hirofumi Arima, Motoi Matsuura, Yutaka Taketani, Toshio Doi and Eiji Takeda : Effect of a novel palatinose-based liquid balanced formula (MHN-01) on glucose and lipid metabolism in male Sprague-Dawley rats after short- and long-term ingestion., Metabolism: Clinical and Experimental, Vol.53, No.8, 977-983, 2004.
(要約)
Postprandial hyperglycemia and hyperinsulinemia are often present in obese subjects with glucose intolerance in whom insufficient early phase insulin secretion and subsequent delayed hyperinsulin response are observed. To address this problem, a novel palatinose-based enteral formula designated as MHN-01 was developed for the prevention of postprandial hyperglycemia and hyperinsulinemia. The effects of MHN-01 on carbohydrate and lipid metabolism in Sprague-Dawley (SD) rats were compared with those of the standard balanced formula (SBF). After a bolus intragastric injection of each formula equivalent to 0.9 g/kg carbohydrate, the peak levels of plasma glucose (PG) and insulin (IRI) in peripheral and portal veins of the MHN-01 group were significantly lower than those of the SBF group. The areas under the curve of PG and IRI in the MHN-01 group were 58.0% and 43.1% of those in the SBF group in the femoral vein and 65.0% and 69.3% in the portal vein, respectively. In the 2-month study, serum levels of IRI and triglyceride in peripheral blood in the MHN-01 group decreased and those in the SBF group increased compared with initial levels. Consequently, both levels in the MHN-01 group were significantly lower than those in the SBF group. In addition, the amount of accumulated fat in abdominal adipose tissue and liver tissue of the MHN-01 group was markedly reduced in comparison to that of the SBF group. Insulin sensitivity, evaluated as glucose infusion rate using the hyperinsulinemic euglycemic clamp technique, in the MHN-01 group was higher than that in the SBF group. Thus, in comparison to SBF, MHN-01 suppressed postprandial hyperglycemia and hyperinsulinemia, reduced visceral fat accumulation, and improved insulin sensitivity. Therefore, human study on the effects of MHN-01 on carbohydrate and lipid metabolism will be recommended to confirm whether MHN-01 may be a useful functional food for the treatment and prevention of insulin resistance.
Seiji Ohashi, Hideharu Abe, Toshikazu Takahashi, Yasuhiko Yamamoto, Masayoshi Takeuchi, Hidenori Arai, Kazuhiro Nagata, Toru Kita, Hiroshi Okamoto, Hiroshi Yamamoto and Toshio Doi : Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy, The Journal of Biological Chemistry, Vol.279, No.19, 19816-19823, 2004.
(要約)
Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.
Hideharu Abe, Takeshi Matsubara, Noriyuki Iehara, Kojiro Nagai, Toshikazu Takahashi, Hidenori Arai, Toru Kita and Toshio Doi : Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end-products (AGEs) stimulation, The Journal of Biological Chemistry, Vol.279, No.14, 14201-14206, 2004.
(要約)
Prolonged exposure to hyperglycemia is now recognized as the most significant causal factor of diabetic complications. Excessive advanced glycation end products (AGEs) as a result of hyperglycemia in tissues or in the circulation may critically affect the progression of diabetic nephropathy. In diabetic nephropathy, glomerulosclerosis is a typical pathologic feature characterized by the increase of the extracellular matrix (ECM). We have reported previously that alpha1 type IV collagen (Col4) is one of the major components of ECM, which is up-regulated by AGEs, and that the overexpression of Col4 is transcriptionally regulated by an unknown transcription factor binding to the promoter. Here we identified this protein as Smad1 by yeast one-hybrid screening. Using chromatin immunoprecipitation and reporter assay, we observed that Smad1 directly regulated transcription for Col4 through the binding of Smad1 to the promoter of Col4. Smad1 was significantly induced along with Col4 in AGE-treated mesangial cells. Moreover, suppression of Smad1 by antisense morpholino resulted in a decrease of AGE-induced Col4 overproduction. To elucidate the interaction between transforming growth factor-beta and Smad1, we investigated whether activin receptor-liked kinase1 (ALK1) was involved in this regulation. AGE stimulation significantly increased the expression of the ALK1 mRNA in mesangial cells. We also demonstrated that Smad1 and ALK1 were highly expressed in human diabetic nephropathy. These results suggest that the modulation of Smad1 expression is responsible for the initiation and progression of diabetic nephropathy and that blocking Smad1 signaling may be beneficial in preventing diabetic nephropathy and other various diabetic complications.
(キーワード)
Activin Receptors, Type I / Activin Receptors, Type II / Animals / Cell Line / Collagen Type IV / DNA-Binding Proteins / Diabetic Nephropathies / Extracellular Matrix Proteins / Gene Library / Glomerular Mesangium / Glycosylation End Products, Advanced / Humans / Mice / Mice, Inbred C57BL / Promoter Regions, Genetic / Smad Proteins / Smad1 Protein / Trans-Activators / Transcription, Genetic / Two-Hybrid System Techniques
Yuji Sakurai, Hideyuki Motohashi, Harumasa Ueo, Satohiro Masuda, Hideyuki Saito, Masahiro Okuda, Noriko Mori, Motokazu Matsuura, Toshio Doi, Atsushi Fukatsu, Osamu Ogawa and Ken-ichi Inui : Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases, Pharmaceutical Research, Vol.21, No.1, 61-67, 2004.
(要約)
Because the urinary excretion of drugs is often decreased in renal diseases, dosage regimens are adjusted to avoid adverse drug reactions. The aim of present study was to clarify the alteration in the levels of renal drug transporters and their correlation with the urinary drug excretion in renal diseases patients. We quantified the mRNA levels of human organic anion transporters (hOATs) by real-time polymerase chain reaction and examined the excretion of the anionic drug, cefazolin, in renal disease patients. Moreover, transport of cefazolin by hOAT1 and hOAT3 were examined using HEK293 transfectants. Among four hOATs, the level of hOAT1 mRNA was significantly lower in the kidney of patients with renal diseases than in the normal controls. The elimination constant of cefazolin showed a significant correlation with the values of phenolsulfonphthalein test and mRNA levels of hOAT3. The uptake study using HEK293 transfectants revealed that cefazolin and phenolsulfonphthalein were transported by hOAT3. These results suggest that hOAT3 plays an important role for anionic drug secretion in patients with renal diseases and that the expression levels of drug transporters may be related to the alteration of renal drug secretion.
(キーワード)
Adult / Aged / Analysis of Variance / Cefazolin / Cell Line / Dose-Response Relationship, Drug / Female / Gene Expression Regulation / Humans / Kidney / Kidney Diseases / Male / Middle Aged / Organic Anion Transport Protein 1 / Organic Anion Transporters / Organic Anion Transporters, Sodium-Independent / Pharmaceutical Preparations / RNA, Messenger / Transfection
Kojiro Nagai, Hidenori Arai, Motoko Yanagita, Takeshi Matsubara, Hiroshi Kanamori, Toru Nakano, Noriyuki Iehara, Atsushi Fukatsu, Toru Kita and Toshio Doi : Growth arrest-specific gene 6 is involved in glomerular hypertrophy in the early stage of diabetic nephropathy, The Journal of Biological Chemistry, Vol.278, No.20, 18229-18234, 2003.
Akira Mizuno, Takashi Murakami, Toshio Doi and Kenji Shima : Effect of leptin on insulin sensitivity in the Otsuka long-Evans Tokushima fatty rat., Regulatory Peptides, Vol.99, No.1, 41-44, 2001.
(要約)
Leptin has been proposed to be a sensor of energy storage in adipose tissues, and is capable of mediating a feedback signal to the hypothalamus, which is involved in the regulation of energy homeostasis and body weight. In order to investigate the issue of whether resistance to the activity of leptin on insulin sensitivity is observed in young Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 8 weeks of age, leptin (50 nmol/kg/h) was administered intravenously for 16 h to OLETF and Long-Evans Tokushima Otsuka (LETO) (lean controls) rats, followed by a measurement of insulin-stimulated glucose uptake in hindlimb muscles during hyperinsulinemic euglycemic clamp technique. In the case of LETO rats, the administration of leptin significantly decreased plasma insulin levels prior to the clamp test, but did not change plasma glucose levels. Furthermore, leptin led to an increase in insulin-stimulated glucose uptake in hindlimb muscles. However, in the case of OLETF rats, leptin administration changed neither plasma insulin levels nor insulin-stimulated glucose uptake. These data demonstrate that OLETF rats at 8 weeks of age have already become resistant to high concentration of peripheral leptin.
(キーワード)
Animals / Blood Glucose / Diabetes Mellitus, Type 2 / Drug Resistance / Humans / Hyperglycemia / インスリン (insulin) / Leptin / Male / Rats / Rats, Inbred OLETF
Kojiro Nagai and Toshio Doi : CIN85: Implications for the Development of Proteinuria in Diabetic Nephropathy., Diabetes, Vol.65, No.12, 3532-3534, 2016.
K Taguchi, Hisami Okumura, A Mizuno, T Nakamura, Mitsuo Shimada, Toshio Doi and E Takeda : Insulin resistance as early sign of hepatic dysfunction in liver cirrhosis, The Journal of Medical Investigation : JMI, Vol.61, No.1.2, 180-189, 2014.
(要約)
Glucose intolerance characterized by postprandial hyperglycemia and hyperinsulinemia is commonly seen in patients with liver cirrhosis (LC). The aim of this study is to clarify the relation between glucose intolerance and disorder of liver function in patients with LC. The 75 g oral glucose tolerance test (75 g OGTT) and the hyperinsulinemic euglycemic clamp combined with 0.2 g/kg oral glucose load (HECGL) were conducted in 61 patients with LC. Based on the results of 75 g OGTT, the 61 patients with LC were divided into groups, 21 (34.4%) patients with normal glucose tolerance (LC-NGT), 12 (19.7%) patients with impaired glucose tolerance (LC-IGT) and 28 (45.9%) patients with diabetes mellitus (LC-DM). Fasting plasma glucose (FPG) level was normal in 50 (82.0%) patients with LC. All patients with LC showed insulin resistance in both peripheral (skeletal and adipose) and hepatic tissues evaluated by HECGL, although significant correlation between the degree of glucose intolerance and the severity of hepatic dysfunction was not observed. Insulin resistance in both liver and peripheral tissues is the early sign in the patients with LC. This fact indicates that nutritional care from early stages of LC would be necessary in the patients.
Masanori Tamaki, Tatsuya Tominaga, Yui Fujita, Taichi Murakami, Seiji Kishi, Hideharu Abe, Kojiro Nagai and Toshio Doi : A Novel All-Trans Retinoic Acid Therapy Directly Suppresses Bone Morphogenetic Protein 4 in Mouse Diabetic Nephropathy, KIDNEY WEEK 2019 American Society of Nephrology, Nov. 2019.
2.
Masanori Tamaki, Taizo Inagaki, Masanori Minato, Fumi Kishi, Seiji Kishi, Taichi Murakami, Kojiro Nagai, Hideharu Abe and Toshio Doi : A case of Helicobacter cinaedi-induced PD-related peritonitis detected by blood culture, APCM-ISPD2019, Sep. 2019.
3.
Masanori Tamaki, Tatsuya Tominaga, Yui Fujita, Seiji Kishi, Taichi Murakami, Kojiro Nagai, Hideharu Abe and Toshio Doi : Mesangial Matrix Expansion Attenuated by All-Trans Retinoic Acid Through Direct Suppression of Bone Morphogenetic Protein 4 in Mouse Diabetic Nephropathy, KIDNEY WEEK 2018 American Society of Nephrology, Oct. 2018.
4.
Yui Fujita, Tatsuya Tominaga, Masanori Tamaki, Taichi Murakami, Seiji Kishi, Kojiro Nagai, Hideharu Abe and Toshio Doi : Palovarotene, Selective Retinoic Receptor- Agonist, Inhibited Both BMP4 and TGF- Signaling Pathways in Diabetic Nephropathy, KIDNEY WEEK 2017 American Society of Nephrology, Nov. 2017.
5.
Masanori Tamaki, Tatsuya Tominaga, Yui Fujita, Seiji Kishi, Taichi Murakami, Kojiro Nagai, Hideharu Abe and Toshio Doi : Glomerulosclerosis Attenuated by Retinoic Acid through Bone Morphogenetic Protein 4 Suppression in Mice with Streptozotocin-Induced Diabetes, KIDNEY WEEK 2017 American Society of Nephrology, Nov. 2017.
6.
Seiji Kishi, Kenji Nishimura, Takaharu Ichimura, Ryuji Morizane, Takaharu Ichimura, Joseph Bonventre and Toshio Doi : Disruption of genome maintenance mechanisms in renal proximal tubular epithelial cells exacerbates human kidney fibrosis, the ASN Kidney Week 2017 Annual Meeting October 31 - November 5 in New Orleans, LA., Nov. 2017.
Hiroyuki Ono, Seiji Kishi, Kojiro Nagai, Taichi Murakami, Hideharu Abe and Toshio Doi : Shunt Nephritis And Pyogenic Spondylitis With A Positive PR3-ANCA Associated With Chronically Infected Ventriculo-Arterial Shunt, the ASN Kidney Week 2016 Annual Meeting, November 15-20 in Chicago, IL., Nov. 2016.
9.
Kojiro Nagai, Tatsuya Tominaga, Taichi Murakami, Eriko Shibata, Seiji Kishi, Motokazu Matsuura, Hideharu Abe and Toshio Doi : In vivo evidence of mTORC1-S6 kinase pathway involvement in the development of glomerulosclerosis in human IgA nephropathy, KIDNEY WEEK 2016 American Society of Nephrology, Nov. 2016.
10.
Yui Fujita, Tatsuya Tominaga, Taichi Murakami, Seiji Kishi, Kojiro Nagai, Hideharu Abe and Toshio Doi : The Role of BMP4 Signal Pathway on the Podocyte Injury in Diabetic Early Stage, ASN Kidney week 2016, Nov. 2016.
11.
Naoki Tokunaga, Kojiro Nagai, Chihiro Inoue, Yusuke Inoue, Saki Akaiwa, Hiroko Yoshida, Takayuki Nakao and Toshio Doi : Utility of clot waveform data in prothrombin time assay as a marker of anticoagulant effects by direct thrombin or Factor Xa inhibitors., International Society for Laboratory Hematology, May 2016.
12.
Tatsuya Tominaga, Toshio Doi and Kanwar S Yashpal : Myo-inositol oxygenase (MIOX) contributes to renal tubular injury through ER stress and a hyaluronic acid (HA) production, American Society of Nephrology Kidney Week 2015, Nov. 2015.
13.
K Yoshikawa, Hideharu Abe, Motokazu Matsuura, Kojiro Nagai, Akira Mima, E Shibara, J Minakuchi and Toshio Doi : High-Density Lipoprotein Cholesterol and Matrix Gla Protein Are Implicated in the Progression of Aortic Calcification through Bone Morphogenetic Protein 4- or Activin-Like Kinase 1-Induced Smad1 Activation in Patients Undergoing Maintenance Hemodialysis., 46th American Society of Nephrology (ASN) Annual Meeting, Nov. 2013.
14.
Tatsuya Tominaga, Hideharu Abe, Kojiro Nagai, Akira Mima, Seiji Kishi, K Jishage, N Fukushima and Toshio Doi : Role of BMP4 for regulating podocyte injury in the diabetic nephropathy., American Society for Cell biology, San Francisco, Dec. 2012.
15.
Masashi Miyoshi, Kojiro Nagai, Takei Kake, Naoshi Fukushima, Motokazu Matsuura, Eriko Shibata, Satoshi Yamada, Kazuhiro Yoshikawa, Akira Mima, Fumi Kishi, Seiji Kishi, Tatsuya Tominaga, Hideharu Abe and Toshio Doi : Expression of Gas6 and Axl in Human IgA Nephropathy. ~A Possible Involvement of Gas6 in Podocyte Injury~, American Society of Nephrology Kidney Week 2012, San Diego, Nov. 2012.
16.
Tatsuya Tominaga, Hideharu Abe, Kojiro Nagai, Seiji Kishi, Akira Mima and Toshio Doi : BMP4 regulates podocyte injury in the diabetic nephropathy, Diabetes, Philadelphia, May 2012.
17.
Seiji Kishi, Hideharu Abe, Kojiro Nagai and Toshio Doi : SOX9 induces irreversible chondrogenic phenotypic change in diabetic nephropathy, the 2011 Annual Meeting of the American Society for Cell Biology, Denver, Dec. 2011.
18.
Tatsuya Tominaga, Hideharu Abe, Kojiro Nagai, Seiji Kishi and Toshio Doi : BMP4 regulates podocyte injury in the diabetic nephropathy, The 1st Asia-Pacific Vascular Biology Meeting, Dec. 2011.
19.
Tatsuya Tominaga, Hideharu Abe, Kojiro Nagai, Seiji Kishi, Taichi Murakami and Toshio Doi : BMP4 regulates podocyte injury in the diabetic nephropathy, Journal of the American Society of Nephrology, Nov. 2011.
20.
Akira Mima, H Arai, T Matsubara, Hideharu Abe, H Kanamori, E Sumi, Tatsuya Tominaga, T Takahashi, Motokazu Matsuura, N Iehara, A Fukatsu, T Kita and Toshio Doi : Angiotensin II type I receptor blocker decreases urinary Smad1, a marker for mesangial matrix expansion in diabetic nephropathy, 2007 World Congress of Nephrology, リオデジャネイロ, Apr. 2007.
21.
A. Kitamura, Hiroyasu Tsukaguchi, Cheong HLL, Shoji Kagami, M Hattori, M Ikeda, K. Nozu, N. Yoshikawa, Toshio Doi, Y Choi and K. Iijima : Genetic scanning for 12 Asian families with steroid resistant nephrotic syndrome (SRN) based on haplotype analysis and computer simulation approach, 37th Annual meeting of American Society of Nephrology, St. Louis, 2004.
22.
A. Kitamura, Hiroyasu Tsukaguchi, Shoji Kagami, M. Hattori, M. Ikeda, M. Honda, K. Nozu, N. Yoshikawa, Yasuhiro Kuroda, Toshio Doi and K. Iijima : Genetic Iinkage analysis of candidate ioci in Japanese families with steroid resistant nephrotic syndrome, 36th Annual meeting of American Society of Nephrology, San Diego, 2003.
岸 誠司, Takaharu Ichimura, Ryuji Morizane, 西村 賢二, 土井 俊夫, Joseph Bonventre : Disruption of genome maintenance mechanisms in renal proximal tubular epithelial cells exacerbates kidney fibrosis, The 61th Annual Meeting of the Japanese Society of Nephrology(Regular submission), 2018年6月.