Maki Urushihara and Yukiko Kinoshita : Renin-Angiotensin System Activation and Extracellular Signal-Regulated Kinases in Glomerulonephritis, 2011.
(キーワード)
renin-angiotensin system / extracellular matrix / glomerulonephritis
学術論文(審査論文):
1.
Mai Nakagawa, Kazumi Nakagawa, Koga Nakai, Ayumu Tominaga, Yoshiro Mori, Takeshi Iwasa, Maki Urushihara, Ichiro Hashimoto and Hisayoshi Morioka : Characteristics of hospital pediatricians and obstetricians/gynecologists working long hours in Tokushima, Japan: A cross-sectional study., PLoS ONE, Vol.19, No.11, e0311653, 2024.
(要約)
The results of this study suggest that many pediatricians and OB/GYNs work long hours, and it is essential to improve their work environment, including task-shifting/task-sharing. Further enhanced recruitment and retention of hospital pediatricians and OB/GYNs is required. A detailed and large-scale study of pediatricians and OB/GYNs' working environments is essential in the future.
Tatsuo Mori, Mutsuki Nakano, Takahiro Tayama, Aya Goji, Yoshihiro Toda, Shinichi Kameyama, Takeshi Mizuguchi, Maki Urushihara and Naomichi Matsumoto : A female case of L1 syndrome that may have developed due to skewedXinactivation., Brain & Development, Vol.46, No.6, 230-233, 2024.
(キーワード)
Humans / Female / X Chromosome Inactivation / Neural Cell Adhesion Molecule L1 / Hydrocephalus / Child, Preschool / Agenesis of Corpus Callosum
Tomoki Hattori, Keisuke Fujioka, Takashi Nagai, Shuji Kondo, Shoji Kagami, Masahiro Hirayama and Maki Urushihara : Intrarenal renin-angiotensin system activation and macrophage infiltrations in pediatric chronic glomerulonephritis., Pediatric Nephrology, 2023.
(要約)
Baseline UAGT and UMCP-1 levels positively correlated with urinary protein levels, scores for mesangial hypercellularity, rate of crescentic formation, and expression levels of AGT and CD68 in renal tissues (p < 0.05). UAGT and UMCP-1 levels were significantly decreased after RAS blockade and immunosuppressant treatment (p < 0.01), which was accompanied by AGT and CD68 (p < 0.01), as well as the magnitude of glomerular injury. Cultured human MCs showed increased MCP-1 messenger ribonucleic acid and protein levels after Ang II treatment (p < 0.01).
Tatsuo Mori, Masamune Sakamoto, Takahiro Tayama, Aya Goji, Yoshihiro Toda, Atsushi Fujita, Takeshi Mizuguchi, Maki Urushihara and Naomichi Matsumoto : A case of epilepsy with myoclonic atonic seizures caused by SLC6A1 gene mutation due to balanced chromosomal translocation., Brain & Development, Vol.45, No.7, 395-400, 2023.
(要約)
The patient was a 4-year-old girl. Mild developmental delay was observed during infancy. At the age of one and a half years, she developed atonic seizures once a month. At 4 years of age, her seizures increased to more than 10 times per hour. An ictal electroencephalogram (EEG) showed a 3-4-Hz spike-and-wave complex, which was consistent with atonic and myoclonic seizures of the trunk, eyelids, and lips. Therefore, EMAtS was diagnosed based on the symptoms and EEG findings. After administration of valproic acid (VPA), the epileptic seizures disappeared immediately. At the age of 5 years and 2 months, the seizures recurred but disappeared again when the dose of VPA was increased. Subsequently, no recurrence was observed until 6 years and 3 months of age on VPA and lamotrigine. Chromosome analysis of the patient disclosed 46,XX,t(3;11)(p25;q13.1)dn. Long-read sequencing of the the patient's genomic DNA revealed that the 3p25.3 translocation breakpoint disrupted the intron 7 of the SLC6A1 gene.
We recently reported on a late preterm infant born at 36 weeks' gestation with serious arrhythmia due to hyperkalemia associated with long-term maternal ritodrine administration. It is unknown whether ritodrine alone increases the risk of neonatal hyperkalemia in infants born at 34-36 weeks' gestation. This single-center, retrospective, cohort study enrolled late preterm infants (34-36 gestational weeks) born between 2004 and 2018. Cases with maternal magnesium sulfate use were not sufficient for statistical analysis and so were excluded from the study. Risk factors for the occurrence of hyperkalemia were determined based on clinical relevance and previous reports. In all, 212 late preterm infants with maternal ritodrine use and 400 infants without tocolysis were included in the study. Neonatal hyperkalemia occurred in 5.7% (12/212) in the ritodrine group and 1.8% (7/400) in the control group. The risk of neonatal hyperkalemia was significantly increased by maternal ritodrine administration with a crude odds ratio (OR) of 3.37 (95% confidence interval [CI]: 1.30-8.69; p < 0.01) and an adjusted OR of 3.71 (95% CI: 1.41-9.74; p < 0.01) on multivariable analysis. Long-term tocolysis (≥28 days) with ritodrine increased the risk of neonatal hyperkalemia with 9.3% (11/118) of infants developing hyperkalemia (adjusted OR 4.86; 95% CI: 1.59-14.83; p < 0.01). Neonatal hyperkalemia was not found within 2 weeks of ritodrine administration. This research suggests that late preterm infants born after long-term ritodrine administration are at risk of neonatal hyperkalemia and require special attention.
Yuki Sakaki, Maki Urushihara, Takashi Nagai, Keisuke Fujioka, Shuji Kondo, Yukiko Kinoshita, Tomoki Hattori and Shoji Kagami : Urinary angiotensin converting enzyme 2 and disease activity in pediatric IgA nephropathy, The Journal of Medical Investigation : JMI, Vol.68, No.3.4, 292-296, 2021.
(要約)
Background : Our previous studies demonstrated that the intrarenal renin-angiotensin system (RAS) status was activated in pediatric patients with chronic glomerulonephritis. In the present study, we tested the hypothesis that angiotensin-converting enzyme 2 (ACE2) expression in the kidney is associated with the development of pediatric IgA nephropathy. Methods : We analyzed urinary ACE2 levels and ACE2 expression in the kidney tissues of pediatric patients with IgA nephropathy treated with RAS blockade. Paired tests were used to analyze changes from the first to the second biopsy. Results : Urinary ACE2 levels were significantly decreased after RAS blockade treatment, accompanied by decreased ACE2 expression levels in kidney tissues, urinary protein levels and mesangial hypercellularity scores. Urinary ACE2 levels at the first biopsy were positively correlated with the ACE2 expression levels. Conclusions : These data suggest that urinary ACE2 is associated with ACE2 expression in the diseased kidney, which correlates with the pathogenesis of IgA nephropathy in pediatric patients. J. Med. Invest. 68 : 292-296, August, 2021.
(キーワード)
Angiotensin-Converting Enzyme 2 / Biopsy / Child / Glomerulonephritis, IGA / Humans / Kidney / Renin-Angiotensin System
Maki Urushihara, Hiroshi Sato, Akira Shimizu, Hitoshi Sugiyama, Hitoshi Yokoyama, Hiroshi Hataya, Kentaro Matsuoka, Takayuki Okamoto, Daisuke Ogino, Kenichiro Miura, Riku Hamada, Satoshi Hibino, Yuko Shima, Tomohiko Yamamura, Koichi Kitamoto, Masayuki Ishihara, Takao Konomoto and Motoshi Hattori : Clinical and histological features in pediatric and adolescent/young adult patients with renal disease: a cross-sectional analysis of the Japan Renal Biopsy Registry (J-RBR)., Clinical and Experimental Nephrology, Vol.25, No.9, 1018-1026, 2021.
(要約)
Only a few studies have investigated epidemiological and clinicopathological information regarding pediatric and adolescent and young adult (AYA) patients with renal disease. The purpose of this study was to clarify the differences and relationship of clinicopathological findings between pediatric and AYA patients using the Japan Renal Biopsy Registry (J-RBR). This cross-sectional study analyzed data from patients registered in the J-RBR between 2007 and 2017. Clinicopathological findings at diagnosis were analyzed for 3,463 pediatric (age < 15 years) and 6,532 AYA (age 15-30 years) patients. Although chronic nephritic syndrome was the most common clinical diagnosis at age > 5 years, nephrotic syndrome was the most frequent diagnosis at age < 4 years. The most common pathological diagnosis as classified by pathogenesis in pediatric patients was primary glomerular disease (except IgA nephropathy), whereas IgA nephropathy was increased in AYA patients. Mesangial proliferative glomerulonephritis was the most common pathological diagnosis as classified by histopathology in both pediatric and AYA patients. Minor glomerular abnormalities were the most frequent histopathologic diagnoses of nephrotic syndrome in childhood, but their frequency decreased with age. To the best of our knowledge, this is the first report of clinicopathological features of pediatric and AYA patients in a large nationwide registry of renal biopsy. There were differences of clinical, pathological and histopathologic findings between pediatric and AYA patients.
Ken-ichi Suga, Issei Imoto, Hiromichi Ito, Takuya Naruto, Aya Gohji, Keita Osumi, Narumi Tokaji, Yukako Homma, Akemi Ono, Yuko Ichihara, Miki Shono, Tatsuo Mori, Maki Urushihara, Ryuji Nakagawa, Yasunobu Hayabuchi and Shoji Kagami : Next-generation sequencing for the diagnosis of patients with congenital multiple anomalies and / or intellectual disabilities, The Journal of Medical Investigation : JMI, Vol.67, No.3, 4, 246-249, 2020.
(要約)
Background : In clinical practice, a large proportion of patients with multiple congenital anomalies and/or intellectual disabilities (MCA / ID) lacks a specific diagnosis. Recently, next-generation sequencing (NGS) has become an efficient strategy for genetic diagnosis of patients with MCA/ID. To review the utility of NGS for the diagnosis of patients with MCA / ID. Patients with MCA/ID were recruited between 2013 and 2017. Molecular diagnosis was performed using NGS-based targeted panel sequencing for 4,813 genes. Promising causative variants underwent confirmation by Sanger sequencing or chromosomal microarray. Eighteen patients with MCA/ID were enrolled in this study. Of them, 8 cases (44%) were diagnosed by targeted panel sequencing. Most of diagnosed patients were able to receive better counseling and more appropriate medical management. NGS-based targeted panel sequencing seems to be an effective testing strategy for diagnosis of patients with MCA/ID. J. Med. Invest. 67 : 246-249, August, 2020.
Maki Urushihara, Shuji Kondo, Yukiko Kinoshita, Natsuko Ozaki, Ariunbold Jamba, Takashi Nagai, Keisuke Fujioka, Tomoki Hattori and Shoji Kagami : (Pro)renin receptor promotes crescent formation via the ERK1/2 and Wnt/β-catenin pathways in glomerulonephritis., American Journal of Physiology, Renal Physiology, Vol.319, No.4, F571-F578, 2020.
(要約)
(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active β-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active β-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the β-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/β-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.
Harrison M. Penrose, Akemi Katsurada, Kayoko Miyata, Maki Urushihara and Ryousuke Satou : STAT1 regulates interferon-γ-induced angiotensinogen and MCP-1 expression in a bidirectional manner in primary cultured mesangial cells., Journal of the Renin-Angiotensin-Aldosterone System : JRAAS, Vol.21, No.3, 1470320320946527, 2020.
(要約)
Intrarenal interferon-γ significantly contributes to the development of glomerular injury in which angiotensinogen and monocyte chemoattractant protein 1 levels are elevated. However, the exact nature of the role that interferon-γ plays in regulating angiotensinogen and monocyte chemoattractant protein 1 expression has not been fully delineated. Therefore, the aim of this study was to investigate the role that interferon-γ plays in angiotensinogen and monocyte chemoattractant protein 1 expression. Primary cultured rat mesangial cells were treated with 0-20 ng/mL interferon-γ for 2, 8 or 24 hours. Expression levels of angiotensinogen, monocyte chemoattractant protein 1, suppressors of cytokine signaling 1, an intracellular suppressor of Janus kinase-signal transducers and activators of transcription signaling and activity of the Janus kinase-signal transducers and activators of transcription pathway were evaluated by reverse transcriptase polymerase chain reaction and western blot analysis. Interferon-γ increased angiotensinogen expression in mesangial cells with maximal augmentation observed following 5 ng/mL interferon-γ at 8 hours of treatment (1.87 ± 0.05, mRNA, relative ratio). Further increases were reduced or absent using higher concentrations of interferon-γ. Following treatments, monocyte chemoattractant protein 1 expression was induced in a linear dose-dependent manner (6.85 ± 0.62-fold by 20 ng/mL interferon-γ at 24 hours). In addition, interferon-γ induced STAT1 phosphorylation and suppressors of cytokine signaling 1 expression in a linear dose-dependent manner. The suppression of STAT1 and suppressors of cytokine signaling 1 expression by small interference RNAs facilitated an increase in interferon-γ-induced angiotensinogen expression, indicating that these two factors negatively regulate angiotensinogen expression. In contrast, the increase in interferon-γ-induced monocyte chemoattractant protein 1 expression was attenuated in STAT1-deficient mesangial cells, suggesting that STAT1 positively regulates monocyte chemoattractant protein 1 expression in mesangial cells. These results demonstrate that while interferon-γ increases both angiotensinogen and monocyte chemoattractant protein 1 expression, STAT1 plays an opposing role in the regulation of each factor in mesangial cells.
Keita Osumi, Ken-ichi Suga, Akemi Ono, Aya Gohji, Tatsuo Mori, Yukiko Kinoshita, Mikio Sugano, Yoshihiro Touda, Maki Urushihara, Ryuji Nakagawa, Yasunobu Hayabuchi, Issei Imoto and Shoji Kagami : Molecular diagnosis of an infant with TSC2/ PKD1 contiguous gene syndrome, Human Genome Variation, Vol.7, No.21, 2020.
(要約)
A 1-month-old Japanese infant with cardiac rhabdomyoma was diagnosed with / contiguous gene syndrome by targeted panel sequencing with subsequent quantitative polymerase chain reaction that revealed gross monoallelic deletion, including parts of two genes: exons 19-42 of and exons 2-46 of . Early molecular diagnosis can help to detect bilateral renal cyst formation and multidisciplinary follow-up of this multisystem disease.
Natsumi Yamamura-Miyazaki, Toshimi Michigami, Kenichi Satomura, Maki Urushihara, Shoji Kagami and Katsusuke Yamamoto : Reduction in urinary angiotensinogen levels and improvement of proteinuria by renin-angiotensin system blockade in pediatric chronic kidney disease patients with very low birth weight., Pediatric Nephrology, Vol.35, No.7, 1307-1314, 2020.
(要約)
Children with low birth weight (LBW) have an increased risk of developing chronic kidney disease (CKD), and no effective strategies have been established to prevent the progression of CKD in these patients. Urinary angiotensinogen (UAGT) may represent a useful marker of intrarenal renin-angiotensin system (RAS) activation, which has been suggested to play a critical role in the development of hypertension and CKD. Herein, we conducted a prospective study to determine whether RAS blockade is beneficial for suppressing the progression of CKD in children with LBW, using UAGT as a surrogate marker of renal impairment. Nine children with CKD (stages: 1-2) who had very low birth weight (VLBW; < 1500 g) were started on RAS blockade with candesartan. We measured blood pressure and laboratory parameters, including urinary concentrations of angiotensinogen, protein, albumin, creatinine (Cr), and estimated glomerular filtration rate (eGFR), before and after candesartan treatment. Birth weight was 712 g (range, 536-800 g). Age at evaluation was 11.6 years (range, 10.3-15.6 years). After candesartan treatment for 47.6 ± 25.0 months, the UAGT to urinary Cr ratio decreased from 61.9 ± 44.7 to 16.8 ± 14.4 μg/g (p = 0.015). The urinary protein to Cr and albumin to Cr ratios also decreased (p = 0.008 and p = 0.012, respectively), whereas there was no significant change in eGFR. RAS blockade reduced UAGT levels and improved proteinuria/albuminuria in children with CKD who had VLBW. Suppression of intrarenal RAS activity may slow the progression of CKD in children with LBW.
Keisuke Fujioka, Takashi Nagai, Yukiko Kinoshita, Maki Urushihara, Yuko Hamasaki, Seiichiro Shishido and Shoji Kagami : Successful treatment with voriconazole combined with amphotericin B-liposome for fluconazole-resistant pulmonary cryptococcosis after renal transplantation., CEN Case Reports, Vol.8, No.4, 261-265, 2019.
(要約)
Cryptococcosis is an invasive fungal infection that is common among organ transplant recipients, and it is challenging to treat among these patients because of their immunocompromised status. Fluconazole (FLCZ) is recommended as a first-line treatment modality for pulmonary cryptococcosis in organ transplant recipients. However, cases of FLCZ resistance among Cryptococcus neoformans isolates have been reported from the Asia Pacific region. Previous studies have reported the efficacy of voriconazole (VRCZ) in patients with FLCZ-resistant fungal infections. Herein, we report a case of FLCZ-resistant pulmonary cryptococcosis after renal transplantation that was successfully treated with VRCZ combined with amphotericin B-liposome (L-AMB). The patient was a-23-year-old woman who underwent living-donor kidney transplantation at age 20 years. She has attended our hospital since before for mental retardation, epilepsy, and dilated cardiomyopathy. At age 23 years, she presented to our hospital with fever and cough. She was diagnosed with pulmonary cryptococcosis based on positive-serum cryptococcal antigen. Chest radiography showed bilateral consolidations. Fosfluconazole (F-FLCZ) was administered, and her condition improved. However, she developed cough and fever again on day 60 of hospitalization. Cryptococcosis recurrence was suspected due to the high degree of cryptococcal antigen titers showed (1:2048) taken on the same day. Therefore, L-AMB was added, and F-FLCZ was substituted with VRCZ. Her condition improved, but L-AMB was discontinued due to hyponatremia, hypokalemia, and elevated serum creatinine. This indicates that VRCZ caused the remission. She was discharged after 6 months of admission. In conclusion, this case shows the efficacy of VRCZ combined with L-AMB for refractory pulmonary cryptococcosis.
Miki Shono, Maki Urushihara, Kenichi Suga, Noriko Watanabe, Takahiko Saijo, Ryuji Nakagawa and Shoji Kagami : Enhanced angiotensinogen expression in neonates during kidney development., Clinical and Experimental Nephrology, Vol.23, No.4, 537-543, 2019.
(要約)
We recently demonstrated that preterm neonates have higher urinary angiotensinogen (AGT) levels than full-term neonates. Here, we tested the hypothesis that enhanced neonatal AGT expression is associated with intrarenal renin-angiotensin system (RAS) status during kidney development. We prospectively recruited neonates born at our hospital and healthy children with minor glomerular abnormalities between April 2013 and March 2017. We measured neonatal plasma and urinary AGT levels at birth and 1 year later and assessed renal AGT expression in kidney tissues from neonates and healthy children using immunohistochemical (IHC) analysis. Fifty-four neonates and eight children were enrolled. Although there were no changes in plasma AGT levels, urinary AGT levels were significantly decreased 1 year after birth. Urinary AGT levels at birth were inversely correlated with gestational age, and urinary AGT levels at birth and 1 year later were inversely correlated with estimated glomerular filtration rate 1 year after birth. IHC analysis showed that renal AGT expression in neonates was higher than that in healthy children and inversely correlated with gestational age. Enhanced AGT expression and urinary AGT excretion may reflect intrarenal RAS activation associated with kidney development in utero.
Shuji Kondo, Sato Matsuura, Jamba Ariunbold, Yukiko Kinoshita, Maki Urushihara, Kenichi Suga, Natsuko Ozaki, Takashi Nagai, Keisuke Fujioka and Shoji Kagami : Expression of NADPH oxidase and production of reactive oxygen species contribute to ureteric bud branching and nephrogenesis., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 93-98, 2019.
(要約)
Ureteric bud branching and nephrogenesis are performed through large-scale proliferation and apoptosis events during renal development. Reactive oxygen species (ROS), produced by NADPH oxidase, may contribute to cell behaviors, including proliferation and apoptosis. We investigated the role of NADPH oxidase expression and ROS production in developing kidneys. Immunohistochemistry revealed that NADPH oxidase componentswere expressed on epithelial cells in ureteric bud branches, as well as on immature glomerular cells and epithelial cells in nephrogenic zones. ROS production, detected by dihydroethidium assay, was strongly observed in ureteric bud branches and nephrogenic zones, corresponding with NADPH oxidase localization. Organ culture of E14 kidneys revealed that the inhibition of NADPH oxidase significantly reduced the number of ureteric bud branches and tips, consistent with reduced ROS production. This was associated with reduced expression of phosphorylated ERK1/2 and increased expression of cleaved caspase-3. Organ culture of E18 kidneys showed that the inhibition of NADPH oxidase reduced nephrogenic zone size, accompanied by reduced ROS production, fewer proliferating cell nuclear antigen-positive cells, lower p-ERK1/2 expression, and increased expression of cleaved caspase-3. These results demonstrate that ROS produced by NADPH oxidase might play an important role in ureteric bud branching and nephrogenesis by regulating proliferation and apoptosis. J.Med. Invest. 66 :93-98, February, 2019.
Tuba M. Ansary, Maki Urushihara, Yoshihide Fujisawa, Sayaka Nagata, Hidenori Urata, Daisuke Nakano, Hitomi Hirofumi, Kazuo Kitamura, Shoji Kagami and Akira Nishiyama : Effects of the selective chymase inhibitor TEI-F00806 on the intrarenal renin-angiotensin system in salt-treated angiotensin I-infused hypertensive mice., Experimental Physiology, Vol.103, No.11, 1524-1531, 2018.
(要約)
What is the central question of this study? Can chymase inhibition prevent angiotensin I-induced hypertension through inhibiting the conversion of angiotensin I to angiotensin II in the kidney? What is the main finding and its importance? Treatment with TEI-F00806 decreased angiotensin II content of the kidney, renal cortical angiotensinogen protein levels and chymase mRNA expression, and attenuated the development of hypertension. The effects of the selective chymase inhibitor TEI-F00806 were examined on angiotensin I (Ang I)-induced hypertension and intrarenal angiotensin II (Ang II) production in salt-treated mice. Twelve-week-old C57BL male mice were given a high-salt diet (4% NaCl + saline (0.9% NaCl)), and divided into three groups: (1) sham + vehicle (5% acetic acid in saline), (2) Ang I (1 μg kg min , s.c.) + vehicle, and (3) Ang I + TEI-F00806 (100 mg kg day , p.o.) (n = 8-10 per group). Systolic blood pressure was measured weekly using a tail-cuff method. Kidney Ang II content was measured by radioimmunoassay. Chronic infusion of Ang I resulted in the development of hypertension (P < 0.001), and augmented intrarenal chymase gene expression (P < 0.05), angiotensinogen protein level (P < 0.001) and Ang II content (P < 0.01) in salt-treated mice. Treatment with TEI-F00806 attenuated the development of hypertension (P < 0.001) and decreased Ang II content of the kidney (P < 0.05), which was associated with reductions in renal cortical angiotensinogen protein levels (P < 0.001) and chymase mRNA expression (P < 0.05). These data suggest that a chymase inhibitor decreases intrarenal renin-angiotensin activity, thereby reducing salt-dependent hypertension.
(キーワード)
Angiotensin I / Angiotensin II / Animals / 血圧 (blood pressure) / Chymases / 高血圧 (hypertension) / Kidney / 男性 (male) / Mice / Peptidyl-Dipeptidase A / レニン·アンジオテンシンシステム (Renin-angiotensin System)
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.
Tomomasa Terada, Maki Urushihara, Takahiko Saijo, Ryuji Nakagawa and Shoji Kagami : (Pro)renin and (pro)renin receptor expression during kidney development in neonates., European Journal of Pediatrics, Vol.176, No.2, 183-189, 2017.
(要約)
Although a recent study demonstrated that the (pro)renin receptor ((P)RR) was highly expressed in the developing kidney during the mouse embryonic development, the mechanism by which (P)RR supports renal development in humans is not fully understood. In this study, we examined the plasma levels of (pro)renin and soluble (P)RR (s(P)RR) in cord blood and neonates as well as (P)RR expression in human kidney tissues. Samples were collected from 57 preterm and 67 full-term human neonates. (Pro)renin and s(P)RR levels were measured using enzyme-linked immunosorbent assays. Additionally, we performed an immunohistochemical (IHC) analysis of kidney tissues from neonates and minor glomerular abnormalities in order to assess (P)RR expression in the kidney. Plasma (pro)renin and s(P)RR levels in cord blood were significantly higher in preterm neonates than in full-term neonates. Four weeks after birth, these differences were no longer evident for either plasma (pro)renin or s(P)RR levels between the two groups. Importantly, plasma (pro)renin and s(P)RR levels in cord blood were inversely correlated with gestational age. Furthermore, IHC indicated that renal expression levels of (P)RR in neonates were stronger than those in minor glomerular abnormalities. (P)RR may play a pivotal role in prenatal renal development in humans. What is Known: · Renal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in pediatric renal disease. · Renal RAS activation plays a key role of renal development during gestation. What is New : · Plasma (pro)renin and soluble (pro)renin receptor (s(P)RR) levels in cord blood were significantly higher in preterm neonates than in full-term neonates. · Immunohistochemical analysis of kidney tissue indicated that renal expression levels of (P)RR in neonates were stronger than in minor glomerular abnormalities.
T Nagai, Maki Urushihara, Yukiko Kinoshita, A Jamba, Shuji Kondo and Shoji Kagami : Differential regulation of angiotensin II-induced extracellular regulated kiase-1/2 and -5 in progressive glomerulonephritis., Nephrology, Vol.21, No.11, 950-958, 2016.
(要約)
Extracellular signal regulated kinase (ERK)1/2 and ERK5 are key kinases of the signalling pathways involved in various cellular responses to kidney injury; however, the mechanistic links between those kinase and renin-angiotensin system (RAS) activations in glomerulonephritis (GN) have not been fully elucidated. In this study, we sought to clarify the potential roles of ERK1/2 and ERK5 via RAS activation in the pathogenesis of GN. A rat model of progressive GN was induced by anti-glomerular basement membrane (GBM) injection and the signal transduction pathway in angiotensin II (Ang II)-induced glomerular pathologic alterations were investigated in primary cultured mesangial cells (MCs). Rats developed typical cellular crescents in glomeruli on day 7 that progressed to severe fibrocellular crescents and glomerulosclerosis on day 28. Strong expression of phospho-ERK1/2 was observed on day 7 and phospho-ERK5 expression was markedly increased on day 28 of GN. An angiotensin II type 1 receptor blocker (ARB) suppressed those augmentations. Moreover, ARB treatment attenuated the increases in macrophage infiltration and PCNA-positive cells observed on day 7 in GN rats, as well as the increase in collagen type 1 expression on day 28. Consistently, MCs stimulated by Ang II showed significant increases in proliferation and the expression of MCP-1 and collagen type 1. Interestingly, while the ERK1/2 inhibitor PD98059 abolished the elevations in MCP-1 expression and cell proliferation, the ERK5 inhibitor BIX02189 abrogated the elevation in collagen type 1 expression. Altogether, these data suggest that ERK1/2 regulates acute inflammatory reactions, while ERK5 promotes the development of RAS-induced chronic glomerular fibrosis activation in GN.
(キーワード)
Angiotensin II / Angiotensin II Type 1 Receptor Blockers / Animals / Disease Models, Animal / Fibrosis / Glomerular Mesangium / Glomerulonephritis / Inflammation / Mitogen-Activated Protein Kinase 3 / Rats / Renin-Angiotensin System / Signal Transduction
Maki Urushihara and Shoji Kagami : Role of the intrarenal renin-angiotensin system in the progression of renal disease., Pediatric Nephrology, Vol.32, No.9, 1471-1479, 2016.
(要約)
The intrarenal renin-angiotensin system (RAS) has many well-documented pathophysiologic functions in both blood pressure regulation and renal disease development. Angiotensin II (Ang II) is the major bioactive product of the RAS. It induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation. In addition, Ang II regulates the gene expression of bioactive substances and activates multiple intracellular signaling pathways that are involved in renal damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, intracellular formation of reactive oxygen species, cell proliferation, and extracellular matrix synthesis, which in turn facilities renal injury. Involvement of angiotensinogen (AGT) in intrarenal RAS activation and development of renal disease has previously been reported. Moreover, studies have demonstrated that the urinary excretion rates of AGT provide a specific index of the intrarenal RAS status. Enhanced intrarenal AGT levels have been observed in experimental models of renal disease, supporting the concept that AGT plays an important role in the development and progression of renal disease. In this review, we focus on the role of intrarenal RAS activation in the pathophysiology of renal disease. Additionally, we explored the potential of urinary AGT as a novel biomarker of intrarenal RAS status in renal disease.
Maki Urushihara, T Nagai, Yukiko Kinoshita, S Nishiyama, Ken-ichi Suga, N Ozaki, A Jamba, Shuji Kondo, H Kobori and Shoji Kagami : Changes in urinary angiotensinogen posttreatment in pediatric IgA nephropathy patients., Pediatric Nephrology, Vol.30, No.6, 975-982, 2015.
(要約)
Recently, we demonstrated that urinary angiotensinogen (AGT) levels are increased and reflect intrarenal renin-angiotensin system (RAS) status in pediatric patients with chronic glomerulonephritis. Therefore, this study was performed to test the hypothesis that urinary AGT (UAGT) levels provide a specific index of intrarenal RAS status associated with RAS blockade treatment in pediatric IgA nephropathy (IgAN) patients. We measured plasma and UAGT levels and urinary transforming growth factor beta (TGF-β) levels, after which we performed immunohistochemical analysis of AGT, angiotensin II (Ang II), and TGF-β in 24 pediatric IgAN patients treated with RAS blockades for 2 years. Paired tests were used to analyze the changes from baseline to study end. Although there was no change in plasma AGT levels, UAGT and TGF-β levels were significantly decreased after RAS blockade, which was accompanied by the expression levels of AGT, Ang II, and TGF-β, as well as the magnitude of glomerular injury. Baseline UAGT levels positively correlated with diastolic blood pressure, urinary protein levels, scores for mesangial hypercellularity, and the expression levels of AGT, Ang II, and TGF-β in renal tissues. These data indicate that UAGT is a useful biomarker of intrarenal RAS activation, which is associated with glomerular injury during RAS blockade in pediatric IgAN patients.
(キーワード)
Adolescent / Angiotensin II / Angiotensin II Type 1 Receptor Blockers / Angiotensin-Converting Enzyme Inhibitors / Angiotensinogen / Biomarkers / Biopsy / Child / Enzyme-Linked Immunosorbent Assay / Female / Glomerulonephritis, IGA / Humans / Immunohistochemistry / Kidney / Male / Predictive Value of Tests / Renin-Angiotensin System / Time Factors / Transforming Growth Factor beta / Treatment Outcome / Urinalysis
Hydrogen peroxide-inducible clone-5 (Hic-5) is a transforming growth factor (TGF)-β1-inducible focal adhesion protein. We previously demonstrated that Hic-5 was localized in mesangial cells and its expression was associated with glomerular cell proliferation and matrix expansion in human and rat glomerulonephritis (GN). In the present study, we first assessed the role of Hic-5 in mesangioproliferative GN by injecting Habu venom into heminephrectomized wild type (Hic-5+/+) and Hic-5-deficient (Hic-5-/-) mice. Hic-5+/+ GN mice exhibited glomerular cell proliferation on day 7. Surprisingly, glomerular cell number and Ki-67-positive cells in Hic-5-/- GN mice were significantly greater than those in Hic-5+/+ GN mice on day 7, although the number of glomerular apoptotic cells and the expression of growth factors (platelet-derived growth factor-BB and TGF-β1) and their receptors were similarly increased in both Hic-5+/+ and Hic-5-/- GN mice. In culture experiments, proliferation assays showed that platelet-derived growth factor-BB and TGF-β1 enhanced the proliferation of Hic-5-/- mesangial cells compared with Hic-5+/+ mesangial cells. In addition, mitogenic regulation by Hic-5 was associated with altered and coordinated expression of cell cycle-related proteins including cyclin D1 and p21. The present results suggest that Hic-5 might regulate mesangial cell proliferation in proliferative GN in mice. In conclusion, modulation of Hic-5 expression might have a potential to prevent mesangial cell proliferation in the acute mitogenic phase of glomerulonephritis.
Masashi Suzue, Maki Urushihara, Ryuji Nakagawa, T Saijo and Shoji Kagami : Urinary angiotensinogen level is increased in preterm neonates., Clinical and Experimental Nephrology, Vol.19, No.2, 293-297, 2015.
(要約)
All components of the renin-angiotensin system (RAS) are abundantly synthesized in the developing kidney, suggesting that the RAS plays an important role in renal development. To examine this system in human neonates, we measured urinary angiotensinogen levels in preterm and full-term neonates and examined the relationship between urinary angiotensinogen levels and gestational age. Urine and plasma samples were collected from 20 preterm and 18 full-term neonates at birth. Angiotensinogen levels were measured using enzyme-linked immunosorbent assay. Plasma angiotensinogen concentrations were not increased in preterm neonates compared with that in full-term neonates (P = 0.7288). However, the urinary angiotensinogen-to-creatinine ratio was significantly higher in preterm neonates compared with that in full-term neonates (P = 0.0011). Importantly, the urinary angiotensinogen-to-creatinine ratio dropped significantly with increasing gestational age (P = 0.0010), whereas the plasma angiotensinogen concentration was not correlated with gestational age (P = 0.7814). These results suggest that urinary angiotensinogen levels may indicate the involvement of intrarenal RAS activation in prenatal renal development.
(キーワード)
Angiotensinogen / Biomarkers / Case-Control Studies / Creatinine / Gestational Age / Humans / Infant, Newborn / Premature Birth / Renin-Angiotensin System / Term Birth
Diabetic nephropathy (DN) is the major cause of end-stage renal failure. Oxidative stress is implicated in the pathogenesis of DN. Nitrosonifedipine (NO-NIF) is a weak calcium channel blocker that is converted from nifedipine under light exposure. Recently, we reported that NO-NIF has potential as a novel antioxidant with radical scavenging abilities and has the capacity to treat vascular dysfunction by exerting an endothelial protective effect. In the present study, we extended these findings by evaluating the efficacy of NO-NIF against DN and by clarifying the mechanisms of its antioxidative effect. In a model of type 2 DN (established in KKAy mice), NO-NIF administration reduced albuminuria and proteinuria as well as glomerular expansion without affecting glucose metabolism or systolic blood pressure. NO-NIF also suppressed renal and systemic oxidative stress and decreased the expression of intercellular adhesion molecule (ICAM)-1, a marker of endothelial cell injury, in the glomeruli of the KKAy mice. Similarly, NO-NIF reduced albuminuria, oxidative stress, and ICAM-1 expression in endothelial nitric oxide synthase (eNOS) knockout mice. Moreover, NO-NIF suppressed urinary angiotensinogen (AGT) excretion and intrarenal AGT protein expression in proximal tubular cells in the KKAy mice. On the other hand, hyperglycemia-induced mitochondrial superoxide production was not attenuated by NO-NIF in cultured endothelial cells. These findings suggest that NO-NIF prevents the progression of type 2 DN associated with endothelial dysfunction through selective antioxidative effects.
(キーワード)
Animals / Antioxidants / Cell Line / Diabetic Nephropathies / Humans / Male / Mice / Mice, Inbred C57BL / ノックアウトマウス (knockout mice) / Nifedipine / Nitric Oxide Synthase Type III / Nitroso Compounds / 酸化ストレス (oxidative stress)
Maki Urushihara, Yusuke Seki, Takahiro Tayama, Takashi Nagai, Yukiko Kinoshita, Ariunbold Jamba, Shuji Kondo and Shoji Kagami : Glomerular angiotensin-converting enzyme 2 in pediatric IgA nephropathy, American Journal of Nephrology, Vol.38, No.5, 355-367, 2013.
(要約)
Angiotensin-converting enzyme (ACE) 2 is a homolog of ACE and is thought to be a potent counter-regulator against ACE activity. However, the role of ACE2 has not been investigated in pediatric patients with IgA nephropathy (IgAN). This study was performed to examine the relationship between ACE2 expression and the development of pediatric IgAN. We performed immunohistochemical analysis of ACE2 and ACE in 39 patients with pediatric IgAN and 14 patients with minor glomerular abnormalities, and elucidated the effects of various cytokines on ACE2 expression in cultured human mesangial cells. ACE2 expression levels in glomeruli and tubules were positively correlated with the mesangial hypercellularity score, while ACE expression levels in glomeruli and tubules are not. Multiple regression analysis showed that the mesangial hypercellularity score correlated with the ACE2 expression level in glomeruli and the urinary protein-creatinine ratio. In IgAN patients not treated with a renin-angiotensin system blocker, ACE2 expression levels in glomeruli were significantly increased compared to patients with minor glomerular abnormalities. IgAN patients treated with a renin-angiotensin system blocker did not show this increase in ACE2 expression. Furthermore, cultured human MC showed increased ACE2 mRNA and protein after treatment with IL-1β, a pro-inflammatory cytokine in IgAN. In fact, glomerular expressions of IL-1β were remarkably increased in patients with IgAN. These data indicate that ACE2 expression in glomeruli is associated with mesangial hypercellularity in early lesions of pediatric IgAN.
N Kishi, Ken-ichi Suga, S Matsuura, Yukiko Kinoshita, Maki Urushihara, Shuji Kondo, E Kitano, M Hatanaka, H Kitamura, T Sato, A Maeda and Shoji Kagami : A case of infantile systemic lupus erythematosus with severe lupus nephritis and EBV infection, CEN Case Reports, Vol.2, No.2, 190-193, 2013.
Maki Urushihara, Yukiko Kinoshita, Shuji Kondo and Shoji Kagami : Involvement of the intrarenal renin-angiotensin system in experimental models of glomerulonephritis., Journal of Biomedicine & Biotechnology, Vol.2012, 601786, 2012.
(要約)
The intrarenal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in the development of glomerulonephritis (GN). Angiotensin II (Ang II) is the biologically active product of the RAS. Locally produced Ang II induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation, regulates the gene expression of bioactive substances, and activates multiple intracellular signaling pathways, leading to tissue damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, cell proliferation, and extracellular matrix synthesis, which facilitates glomerular injury. Previous studies have shown that angiotensin-converting enzyme inhibitors and/or AT1 receptor blockers have beneficial effects in experimental GN models and humans with various types of GN, and that these effects are more significant than their suppressive effects on blood pressure. In this paper, we focus on intrarenal RAS activation in the pathophysiology of experimental models of GN.
Ken-ichi Suga, Shuji Kondo, S Matsuura, Yukiko Kinoshita, Maki Urushihara and Shoji Kagami : Glomerular expression of hydrogen peroxide-inducible clone-5 in human and rat progressive mesangial proliferative glomerulonephritis., Nephron. Experimental Nephrology, Vol.120, No.2, 59-68, 2012.
(要約)
Hydrogen peroxide-inducible clone-5 (Hic-5) is a transforming growth factor-β(1) (TGF-β(1))- and hydrogen peroxide (H(2)O(2))-inducible focal adhesion protein that may be necessary for maintaining the myofibroblastic phenotype in pathological scar formation. To investigate the involvement of Hic-5 in the pathogenesis of glomerulonephritis (GN), we examined the glomerular expression of Hic-5 in human and rat GN as well as the regulation of Hic-5 by TGF-β(1) in vitro. Immunohistochemical analyses showed that the expression of Hic-5 was increased in mesangial cells (MCs) in human mesangial proliferative GN. Hic-5 expression was significantly correlated not only with the levels of α-smooth muscle actin (α-SMA) and TGF-β(1), the accumulation of extracellular matrix, and the number of glomerular cells, but also with the urinary protein level in patients with GN. Glomerular Hic-5 expression increased in parallel with α-SMA expression in a rat model of mesangial proliferative GN. Combined therapy with an angiotensin type I receptor blocker and an antioxidant in this model improved the histology and the expression of Hic-5 and α-SMA. TGF-β(1) upregulated Hic-5 and α-SMA protein levels in human cultured MCs. Our findings suggest that Hic-5 is involved in changes in the MC phenotype to produce abnormal extracellular matrix remodeling in GN.
Maki Urushihara and Hiroyuki Kobori : Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease., International Journal of Clinical Medicine, Vol.2, No.1, 378-387, 2011.
(要約)
Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H(2)O(2)) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H(2)O(2)-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease.
Eros Balam-Ortiz, Adolfo Esquivel-Villarreal, Luis Alfaro-Ruiz, Karol Carrillo, Adela Elizalde, Trinidad Gil, Maki Urushihara, Hiroyuki Kobori and Gerardo Jimenez-Sanchez : Variants and haplotypes in angiotensinogen gene are associated with plasmatic angiotensinogen level in Mexican population., The American Journal of the Medical Sciences, Vol.342, No.3, 205-211, 2011.
(要約)
Two polymorphisms (T-20G and C3389T) and 2 haplotypes (H2 and H8) showed an association with plasma AGT levels in Mexican population.
Maki Urushihara and Shoji Kagami : Urinary angiotensinogen as a biomarker of nephropathy in childhood., International Journal of Nephrology, Vol.2011, 206835, 2011.
(要約)
While most circulating angiotensinogen (AGT) is synthesized in the liver, the kidneys also produce AGT. Recently, we reported that urinary AGT is mainly originated from AGT. Using newly developed human AGT ELISA, we measured urinary AGT levels in chronic glomerulonephritis (GN) patients and patients with type 1 diabetes in childhood. Urinary AGT level was positively correlated with diastolic blood pressure, urinary albumin, urinary protein levels, and urinary occult blood in chronic GN patients. Furthermore, urinary AGT level was significantly increased in chronic GN patients not treated with renin-angiotensin system (RAS) blockers compared with control subjects. Importantly, patients treated with RAS blockers had a marked attenuation of this increase. Also, urinary AGT level was significantly higher in patients with diabetic nephropathy in the premicroalbuminuric phase than in control subjects. These results suggest that urinary AGT reflects intrarenal RAS status in chronic GN and may be an early marker of diabetic nephropathy.
Yoshio Konishi, Akira Nishiyama, Takashi Morikawa, Chizuko Kitabayashi, Mikiko Shibata, Masahiro Hamada, Masatsugu Kishida, Hirofumi Hitomi, Hideyasu Kiyomoto, Takenori Miyashita, Nozomu Mori, Maki Urushihara, Hiroyuki Kobori and Masahito Imanishi : Relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy., Hypertension, Vol.58, No.2, 205-211, 2011.
(要約)
We demonstrated previously that the blood pressure of patients with IgA nephropathy becomes salt sensitive as renal damage progresses. We also showed that increased urinary angiotensinogen levels in such patients closely correlate with augmented renal tissue angiotensinogen gene expression and angiotensin II levels. Here, we investigated the relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy. Forty-one patients with IgA nephropathy consumed an ordinary salt diet (12 g/d of NaCl) for 1 week and a low-salt diet (5 g/d of NaCl) for 1 week in random order. The salt-sensitivity index was calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linking 2 data points obtained during consumption of each diet. The urinary angiotensinogen:creatinine ratio was significantly higher in patients who consumed the ordinary salt diet compared with the low-salt diet (17.5 g/g [range: 7.3 to 35.6 g/g] versus 7.9 g/g [range: 3.1 to 14.2 g/g] of creatinine, respectively; P<0.001). The sodium sensitivity index in our patients positively correlated with the glomerulosclerosis score (r=0.43; P=0.008) and changes in logarithmic urinary angiotensinogen:creatinine ratio (r=0.37; P=0.017) but not with changes in urinary protein excretion (r=0.18; P=0.49). In contrast, changes in sodium intake did not alter the urinary angiotensinogen:creatinine ratio in patients with Ménière disease and normal renal function (n=9). These data suggest that the inappropriate augmentation of intrarenal angiotensinogen induced by salt and associated renal damage contribute to the development of salt-sensitive hypertension in patients with IgA nephropathy.
(キーワード)
Adult / Angiotensinogen / Blood Pressure / Female / Glomerulonephritis, IGA / Humans / Kidney / Male / Middle Aged / Renin-Angiotensin System / Retrospective Studies / Sodium Chloride, Dietary
Maki Shimizu, Takanori Sekiguchi, Natsuko Kishi, Aya Goji, Tomoko Takahashi, Hiroko Kozan, Zenichi Sakaguchi, Yukiko Kinoshita, Sato Matsuura, Ken-ichi Suga, Maki Urushihara, Shuji Kondo, Shoji Kagami and Katsuaki Ohara : A case of a 6-year-old girl with anti-neutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis., Clinical and Experimental Nephrology, Vol.15, No.4, 596-601, 2011.
(要約)
A 6-year-old girl was admitted to our hospital with proteinuria, hematuria, skin rash and joint pain of the lower limbs. Due to rapid progression of renal insufficiency, hemodialysis and peritoneal dialysis were performed. She was diagnosed with rapidly progressive glomerulonephritis. Kidney biopsy showed severe crescent formation (50% of glomeruli) and no deposition of any immunoglobulins or complements. Serologically, anti-neutrophil cytoplasmic autoantibody (ANCA) was negative not only by ELISA against proteinase-3 and myeloperoxidase-ANCA but also by indirect immunofluorescent assay against cytoplasmic and perinuclear ANCA. Anti-glomerular basement membrane antibody was also negative. In the acute phase, proinflammatory cytokines such as soluble tumor necrosis factor receptor 1 (sTNFR1), soluble interleukin (IL)-2 receptor (sIL2R), IL-6 and chemokine IL-8 were elevated. The patient was diagnosed with ANCA-negative pauci-immune crescentic glomerulonephritis (CrGN). Intensive treatment with methylprednisolone pulse therapy, plasma exchange, and multiple drug therapy including prednisolone and cyclophosphamide resulted in histopathological improvement and complete remission of proteinuria. There was a possibility that sTNFR1, sIL2R, IL-6 and IL-8 might be involved in the initiation and progression of ANCA-negative pauci-immune CrGN, and to remove and suppress these cytokines might be an effective way to treat ANCA-negative pauci-immune CrGN.
Maki Urushihara, Naro Ohashi, Kayoko Miyata, Ryousuke Satou, W Omar Acres and Hiroyuki Kobori : Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis., Hypertension, Vol.57, No.3, 586-593, 2011.
(要約)
The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor 2 (CCR2) pathway plays a critical role in the development of antiglomerular basement membrane (anti-GBM) nephritis. We recently showed angiotensin II (Ang II) infusion in rats activated MCP-1 and transforming growth factor-1 (TGF-1), which in turn induced macrophage infiltration of renal tissues. This study was performed to demonstrate that combination therapy with a CCR2 antagonist (CA) and an Ang II type 1 receptor blocker (ARB) ameliorated renal injury in the anti-GBM nephritis model. An anti-GBM nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of MCP-1, angiotensinogen, Ang II, and TGF-1. Treatment with CA alone or ARB alone moderately ameliorated kidney injury; however, the combination treatment with CA and ARB dramatically prevented proteinuria and markedly reduced glomerular crescent formation. The combination treatment also suppressed the induction of macrophage infiltration, MCP-1, angiotensinogen, Ang II, and TGF-1 and reversed the fibrotic change in the glomeruli. Next, primary cultured glomerular mesangial cells (MCs) stimulated by Ang II showed significant increases in MCP-1 and TGF-1 expression. Furthermore, cocultured model consisting of MCs, parietal epithelial cells, and macrophages showed an increase in Ang II-induced cell proliferation and collagen secretion. ARB treatment attenuated these augmentations. These data suggest that Ang II enhances glomerular crescent formation of anti-GBM nephritis. Moreover, our results demonstrate that inhibition of the MCP-1/CCR2 pathway with a combination of ARB effectively reduces renal injury in anti-GBM nephritis.
Akira Nishiyama, Yoshio Konishi, Naro Ohashi, Takashi Morikawa, Maki Urushihara, Isseki Maeda, Masahiro Hamada, Masatsugu Kishida, Hirofumi Hitomi, Nobuo Shirahashi, Hiroyuki Kobori and Masahito Imanishi : Urinary angiotensinogen reflects the activity of intrarenal renin-angiotensin system in patients with IgA nephropathy., Nephrology, Dialysis, Transplantation, Vol.26, No.1, 170-177, 2011.
(要約)
These data indicate that urinary angiotensinogen is a powerful tool for determining intrarenal RAS status and associated renal derangement in patients with IgA nephropathy.
Naro Ohashi, Maki Urushihara, Ryousuke Satou and Hiroyuki Kobori : Glomerular angiotensinogen is induced in mesangial cells in diabetic rats via reactive oxygen species--ERK/JNK pathways., Hypertension Research, Vol.33, No.11, 1174-1181, 2010.
(要約)
Whereas intra-renal angiotensinogen is predominantly localized in proximal tubular cells under basal conditions, it has been previously reported that angiotensinogen expression is induced in glomeruli under pathological conditions. However, there is no detailed information regarding the mechanism of the induced glomerular angiotensinogen. We used genetic pairs of Zucker diabetic fatty (ZDF) obese and lean rats to determine glomerular angiotensinogen expression. The levels of glomerular angiotensinogen immunoreactivity in ZDF obese rats were higher than those in ZDF lean rats. Double staining by IHC or IF with angiotensinogen and Thy1.1 antibodies showed that the majority of angiotensinogen in glomeruli was seen in mesangial cells. The levels of glomerular immunoreactivity for 4-HNE and urinary excretion of 8-isoprostane-markers of ROS-in ZDF obese rats were higher than those in ZDF lean rats. To confirm this system, primary rat mesangial cells were treated with hydrogen peroxide (H₂O₂) to clarify the signal transduction pathway for glomerular angiotensinogen expression. H₂O₂ induced an increase in angiotensinogen expression in a dose- and time-dependent manner, and the H₂O₂-induced upregulation of angiotensinogen was suppressed by catalase. Furthermore, the H₂O₂-induced upregulation of angiotensinogen was inhibited by a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor and a c-Jun N-terminal kinase (JNK) inhibitor, but not inhibited by a p38 MAPK inhibitor. These data suggest that the majority of angiotensinogen was induced in mesangial cells in glomeruli under pathological conditions such as diabetic nephropathy, and angiotensinogen expression in mesangial cells was mediated by H₂O₂ and the subsequent activation of extracellular-regulated kinase (ERK)/JNK pathways.
Hiroyuki Kobori, Maki Urushihara, H Ji Xu, S Gerald Berenson and Gabriel Luis Navar : Urinary angiotensinogen is correlated with blood pressure in men (Bogalusa Heart Study)., Journal of Hypertension, Vol.28, No.7, 1422-1428, 2010.
(要約)
The biomarker, UAGT, may facilitate the identification of individuals that are at increased risk for the development of hypertension and early asymptomatic renal disease.
(キーワード)
Adult / African Continental Ancestry Group / Albuminuria / Angiotensinogen / Blood Pressure / Cardiovascular Diseases / European Continental Ancestry Group / Humans / Hypertension / Hypotension / Kidney / Longitudinal Studies / Male / Proteinuria / Renin-Angiotensin System / Risk Factors / Urinary Tract
Maki Urushihara, Shuji Kondo, Shoji Kagami and Hiroyuki Kobori : Urinary angiotensinogen accurately reflects intrarenal Renin-Angiotensin system activity., American Journal of Nephrology, Vol.31, No.4, 318-325, 2010.
(要約)
We recently reported that immunoreactivity of intrarenal angiotensinogen (AGT) is significantly increased in IgA nephropathy patients. Meanwhile, we have developed direct enzyme-linked immunosorbent assays to measure plasma and urinary AGT (UAGT) in humans. This study was performed to test the hypothesis that UAGT levels are increased in chronic glomerulonephritis patients. We analyzed 100 urine samples from 70 chronic glomerulonephritis patients (26 from IgA nephropathy, 24 from purpura nephritis, 8 from lupus nephritis, 7 from focal segmental glomerulosclerosis, and 5 from non-IgA mesangial proliferative glomerulonephritis) and 30 normal control subjects. UAGT-creatinine ratio (UAGT/UCre) was correlated positively with diastolic blood pressure (p = 0.0326), urinary albumin-creatinine ratio (p < 0.0001), urinary protein-creatinine ratio (p < 0.0001) and urinary occult blood (p = 0.0094). UAGT/UCre was significantly increased in chronic glomerulonephritis patients not treated with renin-angiotensin system (RAS) blockers compared with control subjects (p < 0.0001). Importantly, glomerulonephritis patients treated with RAS blockers had a marked attenuation of this augmentation (p = 0.0021). These data indicate that UAGT are increased in chronic glomerulonephritis patients and treatment with RAS blockers suppressed UAGT. The efficacy of RAS blockade to reduce the intrarenal RAS activity can be confirmed by measurement of UAGT in chronic glomerulonephritis patients.
(キーワード)
Adolescent / Adult / Angiotensinogen / Child / Child, Preschool / Female / Glomerulonephritis / Humans / Kidney / Male / Renin-Angiotensin System / Reproducibility of Results / Young Adult
Maki Urushihara, Masanori Takamatsu, Maki Shimizu, Shuji Kondo, Yukiko Kinoshita, Kenichi Suga, Akiko Kitamura, Sato Matsuura, Masanori Yoshizumi, Toshiaki Tamaki, Hiroshi Kawachi and Shoji Kagami : ERK5 activation enhances mesangial cell viability and collagen matrix accumulation in rat progressive glomerulonephritis., American Journal of Physiology, Renal Physiology, Vol.298, No.1, F167-76, 2010.
(要約)
The mitogen-activated protein kinase (MAPK) cascade plays an important role in the regulation of various cellular functions in glomerulonephritis (GN). Here, we investigated whether extracellular signal-regulated kinase 5 (ERK5), a member of the MAPK family, is involved in the pathogenesis of chronic mesangioproliferative GN, using a rat model induced by uninephrectomy and anti-Thy-1 antibody injection. Immunostaining of kidneys obtained at different time points revealed that phospho-ERK5 was weakly expressed in control glomeruli but dramatically increased in a typical mesangial pattern after 28 and 56 days of GN. A semiquantitative assessment indicated that glomerular phospho-ERK5 expression closely paralleled the accumulation of extracellular matrix (ECM), collagen type I, as well as glomerular expression of reactive oxygen species (ROS) and ANG II. On the other hand, phospho-ERK1/2 expression increased on day 7 during the phase of enhanced mesangial cell (MC) proliferation and decreased thereafter. H(2)O(2) and ANG II each induced ERK5 phosphorylation by cultured rat MCs. Costimulation with both H(2)O(2) and ANG II synergistically increased ERK5 phosphorylation in MCs. Cultured MCs transfected with ERK5-specific small interference RNA showed a significant decrease in H(2)O(2) or ANG II-induced cell viability and soluble collagen secretion compared with control cells. Treatment of GN rats with an ANG II type 1 receptor blocker resulted in significant decreases in phospho-ERK5 expression and collagen accumulation accompanied by remarkable histological improvement. Taken together, these results suggest that MC ERK5 phosphorylation by ANG II or H(2)O(2) enhances cell viability and ECM accumulation in an experimental model of chronic GN.
Shintaro Yasue, Hiroaki Masuzaki, Sadanori Okada, Takako Ishii, Chisayo Kozuka, Tomohiro Tanaka, Junji Fujikura, Ken Ebihara, Kiminori Hosoda, Akemi Katsurada, Naro Ohashi, Maki Urushihara, Hiroyuki Kobori, Naoki Morimoto, Takeshi Kawazoe, Motoko Naitoh, Mitsuru Okada, Hiroshi Sakaue, Shigehiko Suzuki and Kazuwa Nakao : Adipose tissue-specific regulation of angiotensinogen in obese humans and mice: impact of nutritional status and adipocyte hypertrophy., American Journal of Hypertension, Vol.23, No.4, 425-431, 2010.
(要約)
BACKGROUND: The adipose tissue renin-angiotensin system (RAS) has been implicated in the pathophysiology of obesity and dysfunction of adipose tissue. However, neither regulation of angiotensinogen (AGT) expression in adipose tissue nor secretion of adipose tissue-derived AGT has been fully elucidated in humans. METHODS: Human subcutaneous abdominal adipose tissue (SAT) biopsies were performed for 46 subjects with a wide range of body mass index (BMI). Considering the mRNA level of AGT and indices of body fat mass, the amount of adipose tissue-derived AGT secretion (A-AGT-S) was estimated. Using a mouse model of obesity and weight reduction, plasma AGT levels were measured with a newly developed enzyme-linked immunosorbent assay (ELISA), and the contribution of A-AGT-S to plasma AGT levels was assessed. RESULTS: A-AGT-S was substantially increased in obese humans and the value was correlated with the plasma AGT level in mice. A-AGT-S and plasma AGT were higher in obese mice, whereas lower in mice with weight reduction. However, the AGT mRNA levels in the liver, kidney, and aorta were not altered in the mouse models. In both humans and mice, the AGT mRNA levels in mature adipocytes (MAs) were comparable to those in stromal-vascular cells. Coulter Multisizer analyses revealed that AGT mRNA levels in the MAs were inversely correlated with the average size of mature adipocytes. CONCLUSIONS: This study demonstrates that adipose tissue-derived AGT is substantially augmented in obese humans, which may contribute considerably to elevated levels of circulating AGT. Adipose tissue-specific regulation of AGT provides a novel insight into the clinical implications of adipose tissue RAS in human obesity.
Toshie Saito, Maki Urushihara, Yumiko Kotani, Shoji Kagami and Hiroyuki Kobori : Increased urinary angiotensinogen is precedent to increased urinary albumin in patients with type 1 diabetes., The American Journal of the Medical Sciences, Vol.338, No.6, 478-480, 2009.
(要約)
Thus, in patients, an increase in urinary angiotensinogen levels is observed, and this increase is precedent to an increase in urinary albumin levels, suggesting that urinary angiotensinogen may function as an early marker of diabetic nephropathy.
(キーワード)
Adolescent / Albuminuria / Angiotensinogen / Animals / Case-Control Studies / Diabetes Mellitus, Type 1 / Diabetic Nephropathies / Enzyme-Linked Immunosorbent Assay / Female / Humans / Male / Rats / Renin-Angiotensin System / Time Factors
Ryousuke Satou, A Romer Gonzalez-Villalobos, Kayoko Miyata, Naro Ohashi, Maki Urushihara, W Omar Acres, Gabriel L Navar and Hiroyuki Kobori : IL-6 augments angiotensinogen in primary cultured renal proximal tubular cells., Molecular and Cellular Endocrinology, Vol.311, No.1-2, 24-31, 2009.
(要約)
In human kidneys, the mechanisms underlying angiotensinogen (AGT) augmentation by interleukin 6 (IL-6) are poorly understood and the only information available is in HK-2, immortalized human renal proximal tubular epithelial cells. Therefore, the present study was performed to elucidate the effects of IL-6 on AGT expression in primary cultured human renal proximal tubular epithelial cells (RPTEC) after characterization of HK-2 and RPTEC. RPTEC showed low basal AGT mRNA (11+/-1%) and protein (7.0+/-0.9%) expression, high IL-6 receptor (IL-6R) expression (282+/-17%), and low basal NF-kappaB (43+/-7%) and STAT3 (43+/-7%) activities compared to those in HK-2. In RPTEC, AGT mRNA and protein expressions were enhanced by IL-6 (172+/-31% and 378+/-39%, respectively). This AGT augmentation was attenuated by an IL-6R antibody. STAT3 phosphorylation (366+/-55% at 30min) and translocation were enhanced by IL-6. The AGT augmentation was attenuated by a STAT3 inhibitor. These data indicate that IL-6 increases AGT expression via STAT3 pathway in RPTEC.
Susumu Ogawa, Hiroyuki Kobori, Naro Ohashi, Maki Urushihara, Akira Nishiyama, Takefumi Mori, Tsuneo Ishizuka, Kazuhiro Nako and Sadayoshi Ito : Angiotensin II Type 1 Receptor Blockers Reduce Urinary Angiotensinogen Excretion and the Levels of Urinary Markers of Oxidative Stress and Inflammation in Patients with Type 2 Diabetic Nephropathy., Biomarker Insights, Vol.4, 97-102, 2009.
(要約)
ARB-induced blockade of the abovementioned vicious cycle contributes to the renoprotective effects of ARBs in DN. The urinary levels of AGT could represent a predictive factor for reduced ACR in patients receiving ARB treatment.
Naro Ohashi, Akemi Katsurada, Kayoko Miyata, Ryousuke Satou, Toshie Saito, Maki Urushihara and Hiroyuki Kobori : Role of activated intrarenal reactive oxygen species and renin-angiotensin system in IgA nephropathy model mice., Clinical and Experimental Pharmacology & Physiology, Vol.36, No.8, 750-755, 2009.
(要約)
1. Using HIGA (high IgA of ddY) mice as an IgA nephropathy model and BALB/c mice as controls, we demonstrated that reactive oxygen species (ROS) and the renin-angiotensin system (RAS) were activated in kidneys of HIGA mice. However, it was difficult to establish an association between renal damage and changes in ROS and the RAS. Therefore, the present study was performed to determine whether renal injury is associated with changes in ROS and the RAS in HIGA mice. 2. Male HIGA mice were divided into four groups of 10 each: (i) untreated mice (HIGA + null); (ii) mice treated with the angiotensin AT(1) receptor antagonist olmesartan (5 mg/kg per day; HIGA + OLM); (iii) mice treated with the superoxide dismutase mimetic tempol (50 mg/kg per day; HIGA + Tempol); and (iv) mice treated with RAS-independent antihypertensive drugs (30 mg/kg per day hydralazine, 0.6 mg/kg per day reserpine and 12 mg/kg per day hydrochlorothiazide; HIGA + HRH). Mice were treated for 5 weeks. 3. Systolic blood pressure decreased significantly in the HIGA + OLM and HIGA + HRH groups, but not in the HIGA + Tempol group, compared with HIGA + null mice. The expression of two ROS markers (4-hydroxy-2-nonenal and heme oxygenase-1) and angiotensin II as a marker of the RAS decreased significantly in HIGA + OLM and HIGA + Tempol mice, but not in HIGA + HRH mice, compared with HIGA + null mice. As a marker of renal damage, mesangial matrix expansion and the desmin-positive area decreased significantly in the HIGA + OLM and HIGA + Tempol groups, but not in HIGA + HRH group, compared with the HIGA + null group. 4. These data suggest that intrarenal ROS and RAS activation play a pivotal role in the development of IgA nephropathy model mice, from the early phase, independent of blood pressure.
(キーワード)
Angiotensin II Type 1 Receptor Blockers / Animals / Blood Pressure / Blotting, Western / Cyclic N-Oxides / Disease Models, Animal / Glomerulonephritis, IGA / Imidazoles / Immunoglobulin A / Immunohistochemistry / Kidney Glomerulus / Male / Mice / Mice, Inbred Strains / Reactive Oxygen Species / Receptor, Angiotensin, Type 1 / Renin-Angiotensin System / Spin Labels / Tetrazoles
N Ohashi, Maki Urushihara and H Kobori : Activated intrarenal reactive oxygen species and renin angiotensin system in IgA nephropathy., Italian Journal of Urology and Nephrology, Vol.61, No.1, 55-66, 2009.
(要約)
Immunoglobulin A (IgA) nephropathy is recognized worldwide as the most common primary glomerulopathy. Although the mechanisms underlying the development of IgA nephropathy are gradually being clarified, their details remain unclear, and a radical cure for this condition has not yet been established. It has been clinically demonstrated that the immunoreactivities of intrarenal heme oxygenase-1 (HO-1) and 4-hydroxy-2-nonenal (4-HNE) markers of reactive oxygen species (ROS) and those of intrarenal angiotensinogen (AGT) and angiotensin II (Ang II) markers of renin angiotensin system (RAS) in IgA nephropathy patients were significantly increased as compared to those of control subjects. In an animal study, high IgA of ddY (HIGA) mice were used as an IgA nephropathy model and compared with BALB/c mice, which served as the control. The levels of markers for ROS (urinary 8-isoprostane and intrarenal 4-HNE), RAS (intrarenal AGT and Ang II), and renal damage in the HIGA mice were significantly increased as compared to those in the BALB/c mice. Moreover, an interventional study using HIGA mice demonstrated that the expressions of 2 lines of intrarenal ROS markers (4-HNE and HO-1), 2 lines of intrarenal RAS markers (AGT and Ang II) and renal damage decreased significantly in HIGA mice receiving treatment with the Ang II receptor blocker olmesartan but not in HIGA mice receiving treatment with RAS-independent antihypertensive drugs (hydralazine, reserpine, and hydrochlorothiazide) when compared with HIGA mice that were not treated. These data suggest that intrarenal ROS and RAS activation plays a pivotal role in the development of IgA nephropathy.
(キーワード)
Aldehydes / Angiotensin II / Angiotensinogen / Animals / Biological Markers / Cysteine Proteinase Inhibitors / Evidence-Based Medicine / Glomerulonephritis, IGA / Heme Oxygenase-1 / Humans / Mice / Reactive Oxygen Species / Renin-Angiotensin System / Vasoconstrictor Agents
(文献検索サイトへのリンク)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19417726
Hiroyuki Kobori, Brent A Alper, Rajesh Shenava, Akemi Katsurada, Toshie Saito, Naro Ohashi, Maki Urushihara, Kayoko Miyata, Ryousuke Satou, Lee L Hamm and Gabriel L Navar : Urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertensive patients., Hypertension, Vol.53, No.2, 344-350, 2008.
(要約)
We reported previously that urinary angiotensinogen (UAGT) levels provide a specific index of the intrarenal renin-angiotensin system (RAS) status in angiotensin II-dependent hypertensive rats. To study this system in humans, we recently developed a human angiotensinogen ELISA. To test the hypothesis that UAGT is increased in hypertensive patients, we recruited 110 adults. Four subjects with estimated glomerular filtration levels <30 mL/min per 1.73 m(2) were excluded because previous studies have already shown that UAGT is highly correlated with estimated glomerular filtration in this stage of chronic kidney disease. Consequently, 106 paired samples of urine and plasma were analyzed from 70 hypertensive patients (39 treated with RAS blockers [angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers; systolic blood pressure: 139+/-3 mm Hg] and 31 not treated with RAS blockers [systolic blood pressure: 151+/-4 mm Hg]) and 36 normotensive subjects (systolic blood pressure: 122+/-2 mm Hg). UAGT, normalized by urinary concentrations of creatinine, were not correlated with race, gender, age, height, body weight, body mass index, fractional excretion of sodium, plasma angiotensinogen levels, or estimated glomerular filtration. However, UAGT/urinary concentration of creatinine was significantly positively correlated with systolic blood pressure, diastolic blood pressure, urinary albumin:creatinine ratio (r=0.5994), and urinary protein:creatinine ratio (r=0.4597). UAGT/urinary concentration of creatinine was significantly greater in hypertensive patients not treated with RAS blockers (25.00+/-4.96 microg/g) compared with normotensive subjects (13.70+/-2.33 microg/g). Importantly, patients treated with RAS blockers exhibited a marked attenuation of this augmentation (13.26+/-2.60 microg/g). These data indicate that UAGT is increased in hypertensive patients, and treatment with RAS blockers suppresses UAGT, suggesting that the efficacy of RAS blockade to reduce the intrarenal RAS activity can be assessed by measurements of UAGT.
Naro Ohashi, Akemi Katsurada, Kayoko Miyata, Ryousuke Satou, Toshie Saito, Maki Urushihara and Hiroyuki Kobori : Activation of reactive oxygen species and the renin-angiotensin system in IgA nephropathy model mice., Clinical and Experimental Pharmacology & Physiology, Vol.36, No.5-6, 509-515, 2008.
(要約)
1. Although IgA nephropathy is the most common form of primary glomerulopathy, the detailed mechanisms underlying its development remain uncertain. 2. In the present study, we used male high IgA strain of ddY (HIGA) mice as the IgA nephropathy model and age-matched male BALB/c mice as the control. Recent studies have demonstrated that reactive oxygen species (ROS)-dependent enhancement of the renin-angiotensin system (RAS) plays a potential role in the development and progression of renal injury. Therefore, in the present study we periodically measured the systolic blood pressure (SBP) of mice over the period 21-25 weeks of age and estimated markers for ROS, RAS and renal damage after mice had been killed at 25 weeks of age. 3. Markers for ROS (urinary 8-isoprostane excretion and renal 4-hydroxy-2-nonenal accumulation), RAS (renal angiotensinogen protein expression, urinary angiotensinogen excretion and renal angiotensin II) and renal damage (desmin-positive area and urinary protein excretion), as well as SBP, were significantly increased in HIGA mice compared with control BALB/c mice. 4. The data suggest that both ROS and the RAS are activated at an early phase in IgA nephropathy model mice.
(キーワード)
Age Factors / Angiotensins / Animals / Blood Pressure / Disease Models, Animal / Glomerulonephritis, IGA / Male / Mesangial Cells / Mice / Mice, Inbred BALB C / Reactive Oxygen Species / Renin-Angiotensin System
Shuji Kondo, Maki Shimizu, Maki Urushihara, Koichiro Tsuchiya, Masanori Yoshizumi, Toshiaki Tamaki, Akira Nishiyama, Hiroshi Kawachi, Fujio Shimizu, Quinn T. Mark, Lambeth J. David and Shoji Kagami : Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progression mesangioproliferative glomerulonephritis in the rat, Journal of the American Society of Nephrology, Vol.17, No.3, 783-794, 2006.
(要約)
Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-beta1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.
(キーワード)
Angiotensin II Type 1 Receptor Blockers / Animals / Antioxidants / Biopsy, Needle / Blotting, Western / Disease Models, Animal / Disease Progression / Drug Therapy, Combination / Female / Glomerulonephritis, Membranoproliferative / Immunohistochemistry / Male / Probability / Probucol / Proteinuria / Rats / Rats, Sprague-Dawley / Sensitivity and Specificity
Maki Urushihara, Shoji Kagami, Michinori Ito, Koji Yasutomo, Shuji Kondo, Akiko Kitamura, Akiyoshi Takahashi and Yasuhiro Kuroda : Transforming growth factor-β in renal disease with glycogen storage disease I, Pediatric Nephrology, Vol.19, No.6, 676-678, 2004.
(要約)
We report a 14-year-old patient with Japanese glycogen storage disease I (GSD-I) who was found to have proteinuria. Renal biopsy revealed massive tubular atrophy and interstitial fibrosis with mononuclear cell infiltration, but the glomeruli were almost normal. The epithelial cells of tubules contained periodic acid-Schiff-positive glycogen deposits digested by diastase. In an immunohistological study, transforming growth factor (TGF)-beta expression was increased in tubular epithelial cells compared with a normal control kidney specimen. These data suggest that increased TGF-beta expression is involved in the pathophysiology of renal interstitial fibrosis in a patient with GSD-I.
Maki Urushihara, Shoji Kagami, Koji Yasutomo, Michinori Ito, Shuji Kondo, Akiko Kitamura, Dag Malm, Helle Klenow, Oiviind Nilssen and Yasuhiro Kuroda : Sisters with α-mannosidosis and systemic lupus erythematosus, European Journal of Pediatrics, Vol.163, No.4-5, 192-195, 2004.
(要約)
Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). Here, we report two sisters with alpha-mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of alpha-mannosidosis and SLE are discussed with regard to both clinical and molecular findings. CONCLUSION: alpha-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.
Shuji Kondo, Shoji Kagami, Maki Shimizu, Akiko Kitamura, Maki Urushihara, Nobuo Satake, Keisuke Izumi and Yasuhiro Kuroda : The role of mast cells in acute tubulo-interstitial nephritis with uveitis, European Journal of Pediatrics, Vol.162, No.7-8, 496-499, 2003.
(要約)
We describe the clinicopathological characteristics of two patients with acute tubulo-interstitial nephritis with uveitis (TINU) with mast cells infiltrating the interstitium. The pathogenesis of TINU remains unknown, but a T-cell-mediated immune response was suggested to be involved. Recent studies have shown that infiltrating mast cells are closely associated with the development of renal interstitial fibrosis in glomerulonephritis. To address the role of mast cells in the renal interstitial injury in TINU, immunohistochemical studies were performed in renal biopsy sections using anti-human mast cell tryptase antibody specific for mast cells. In addition, we tried to detect CD68-positive macrophages to compare with the localisation of mast cells within the renal interstitium. Mast cells and macrophages could be detected in renal interstitial lesions of both patients. Massive infiltration of macrophages into interstitial lesions was observed, whereas mast cells were detected in a sporadic rather than a clustered manner, and associated with fibrotic lesions. Repeat renal biopsy findings suggested the involvement of these cells in the renal interstitial injury because the number of infiltrating mast cells and macrophages in the interstitium decreased with the improvements in clinical symptoms and pathological lesions. CONCLUSION: The present study showed that mast cells might play an important role in the development of renal interstitial injury in tubulo-interstitial nephritis with uveitis.
Shoji Kagami, Maki Urushihara, Shuji Kondo, Hayashi Toshihiko, Hiroko Yamano, Loster Kiemens, Vossmeyer Dorte, Reutter Werner and Yasuhiro Kuroda : Effects of Anti-α1 Integrin Subunit Antibody on Anti-Thy-1 Glomerulonephritis, Laboratory Investigation; a Journal of Technical Methods and Pathology, Vol.82, No.9, 1219-1227, 2002.
(要約)
alpha1beta1 integrin is a potential collagen-binding extracellular matrix receptor that mediates collagen-dependent cell adhesion, proliferation, migration, and collagen matrix assembly and thereby may participate in the wound healing and pathologic scarring observed in some damaged organs. To clarify the role of alpha1beta1 integrin predominantly expressed on the mesangial cell (MC) surface in nephritic glomeruli, we investigated the involvement of MC-alpha1beta1 integrin in rat anti-Thy-1 glomerulonephritis (GN) by administering function-blocking monoclonal mouse anti-rat alpha1 integrin subunit antibody (anti-alpha1 Ab). Assay of collagen types I and IV mixed gel contraction, an in vitro model of pathologic collagen matrix remodeling, with function-blocking anti-alpha1 Ab and anti-beta1 Ab, revealed that collagen I and IV matrix reorganization is mediated by MC-alpha1beta1 integrin. In addition, conditioned medium from isolated Day 3 anti-Thy-1 nephritic glomeruli showed increased activity of MC-alpha1beta1 integrin-induced mixed collagen gel contraction as compared with that from isolated normal rat glomeruli. Treatment of Day 3 conditioned medium with anti-platelet-derived growth factor-BB antibody significantly inhibited conditioned media-induced gel contraction, whereas treatment with anti-transforming growth factor-beta antibody did not have a significant effect. Rats that received anti-alpha1 Ab from the left renal artery 3 days after anti-Thy-1 GN induction showed significant decreases of glomerular hypercellularity and mesangial matrix accumulation, including collagen I and IV in the left kidney, compared with those rats in which the left kidney received control mouse IgG1. These results suggest that MC-alpha1beta1 integrin is an important extracellular matrix receptor mediating mesangial remodeling characterized by MC proliferation and mesangial matrix reorganization in anti-Thy-1 GN. Platelet-derived growth factor-BB may be involved in early collagen matrix reorganization leading to pathologic mesangial remodeling in this GN model.
Maki Urushihara, Shoji Kagami, Takeshi Kuhara, Toshiaki Tamaki and Yasuhiro Kuroda : Glomerular distribution and gelatinolytic activity of natrix metalloproteinases in human glomerulonephritis., Nephrology, Dialysis, Transplantation, Vol.17, No.7, 1189-1196, 2002.
(要約)
Matrix metalloproteinases (MMPs) have been implicated in the development of glomerular injury in rat experimental glomerulonephritis (GN). However, the significance of MMPs in human GN remains obscure. In order to evaluate the role of MMPs in human GN, we examined the glomerular distribution and gelatinolytic activities of MMP-2 and MMP-9 in human GN. We performed immunohistochemistry with polyclonal anti-MMP-2 and MMP-9 antibodies, and analysed gelatin zymograms of five isolated glomeruli from various types of human renal disease. The renal specimens investigated were from normal kidneys (n=5), IgA nephritis (n=20), Henoch-Schönlein nephritis (n=4), non-IgA mesangial proliferative GN (n=9), lupus nephritis (n=6), acute poststreptococcal GN (APSGN) (n=4) and diabetic nephropathy (DN) (n=4). MMP-2 immunoreactivity was not detected in normal controls or in any type of GN. MMP-9 staining, which was almost negative in normal glomeruli, was increased mainly in the mesangial region and corresponded to the level of glomerular cell proliferative changes in mesangial proliferative GN (IgA nephritis, Henoch-Schönlein nephritis, non-IgA mesangial proliferative GN and lupus nephritis). Positive but weak staining for MMP-9 was observed in mesangial areas in DN. In addition, double immunostaining showed that MMP-9 is colocalized in scattered neutrophils within diseased glomeruli in APSGN. MMP-9 gelatinolytic activity in five normal glomeruli was weakly detected. Consistent with the levels of immunostaining, MMP-9 glomerular activity was dramatically increased in nephritic glomeruli with IgA nephritis, lupus nephritis and DN. The gelatinolytic activity of MMP-2 was occasionally detectable in nephritic glomeruli. These results strongly suggest that MMP-9 plays an important role in abnormal mesangial proliferative changes in human GN.
Akiko Kitamura, Shoji Kagami, Maki Urushihara, Syuji Kondo, Masanori Yoshizumi, Toshiaki Tamaki and Yasuhiro Kuroda : Endothelin-1 is a potent stimulator of a1b1 integrin-mediated collagen matrix remodeling by rat mesangial cells., Biochemical and Biophysical Research Communications, Vol.299, 555-561, 2002.
64.
Koji Yasutomo, Horiuchi Takahiko, Shoji Kagami, Hiroshi Tsukamoto, Chinami Hashimura, Maki Urushihara and Yasuhiro Kuroda : Mutation in DNASE I in people with systemic lupus erythematosus, Nature Genetics, Vol.28, No.4, 313-314, 2001.
(要約)
Systemic lupus erythematosus (SLE) is a highly prevalent human autoimmune diseases that causes progressive glomerulonephritis, arthritis and an erythematoid rash. Mice deficient in deoxyribonuclease I (Dnase1) develop an SLE-like syndrome. Here we describe two patients with a heterozygous nonsense mutation in exon 2 of DNASE1, decreased DNASE1 activity and an extremely high immunoglobulin G titer against nucleosomal antigens. These data are consistent with the hypothesis that a direct connection exists between low activity of DNASE1 and progression of human SLE.
Glomerular mesangial cell (MC) proliferation, hypertrophy, and abnormal matrix remodeling characterized by increased expression of fibronectin, laminin and collagen type IV, and neoexpression of collagen I and III are the main biological features of progressive glomerulonephritis (GN). Especially, persistent pathological matrix remodeling may lead to glomerular scar formation (glomerular scarring). We reported recently that alpha1beta1 integrin, a major collagen receptor for MCs, may be a potential adhesion molecule for MC-mediated pathological collagen matrix remodeling in GN. To address further the direct role of alpha1beta1 integrin in MC behavior, such as cell growth and matrix remodeling, alpha1beta1 integrin was overexpressed in MCs by transfecting an expression vector containing a full-length rat alpha1 integrin cDNA. Flow cytometry and immunoprecipitation analysis were applied for selection of transfectants with a stable expression of the alpha1 integrin subunit. The effect of alpha1beta1 integrin overexpression on MC biology was examined with a 3H-thymidine incorporation assay, flow cytometric analysis of cell size and DNA content, Western blot analysis of a cyclin-dependent-kinase inhibitor, p27Kip1, alpha-smooth muscle actin expression, and a collagen gel contraction assay. The alpha1 transfectants displayed a dramatic inhibition of 3H-thymidine incorporation as compared with the mock transfectants. Increased expression of the alpha1 subunit inversely correlated with cell cycle progression and paralleled the expression of p27Kip1 and alpha-smooth muscle actin, as well as the cell size in MCs. In addition, the alpha1-transfectants were able to enhance collagen matrix reorganization effectively. These results indicate that MC-alpha1beta1 integrin expression is a critical determinant of MC phenotypes, including cell growth, cell size, and collagen matrix remodeling ability, and thereby contributes to scar matrix remodeling (sclerosis) in GN.
Shoji Kagami, Shuji Kondo, Loster Klemens, Werner Reutter, Maki Urushihara, Akiko Kitamura, Shoko Kobayashi and Yasuhiro Kuroda : Collagen Type I Modulates the Platelet-Derived Growth Factor (PDGF) Regulation of the Growth and Expression of β1 Integrins by Rat Mesangial Cells, Biochemical and Biophysical Research Communications, Vol.252, No.3, 728-732, 1998.
(要約)
Mesangial cell (MC) proliferation and the deposition of collagen type I (collagen I) are the major pathological features in many types of glomerulonephritis (GN). Recent work suggested that beta-integrins play a critical role in the cell proliferation and extracellular matrix (ECM) remodeling observed in tissue repair after injury. To examine the involvement of beta-integrins in MC proliferation in association with the interaction of MCs with pathological collagen I, we investigated the effect of a prominent mitogen, platelet-derived growth factor-BB (PDGF-BB) on the growth and expression of beta-integrins by MCs cultured on plastic or in a three-dimensional collagen I gel. Immunoprecipitation using 35S-metabolic labeling, flow cytometry and a 3H-thymidine-uptake analysis demonstrated that PDGF-BB stimulated the cell mitogenicity and the expression of alpha5beta1 integrin (a fibronectin receptor), but not alpha1beta1 integrin (a collagen and laminin receptor) of MCs on plastic, in a dose-dependent manner. In contrast, MCs in the collagen I gels showed no significant changes in mitogenicity or alpha1beta1 and alpha5beta1 integrin expression, but increased alpha1beta1 integrin-mediated gel contraction was observed after PDGF-BB stimulation. Thus, the parallel up-regulation of MC-mitogenicity and alpha5beta1 integrin expression by PDGF-BB suggested that alpha5beta1 integrin is an important ECM receptor involved in the proliferative phenotype of MC. A spatial interaction between MCs and pathological collagen I in GN may influence the PDGF regulation of the MC phenotype regarding the cell growth and the expression of beta1 integrins.
Sato Matsuura, Shuji Kondo, Ken-ichi Suga, Yukiko Kinoshita, Maki Urushihara and Shoji Kagami : Expression of focal adhesion proteins in the developing rat kidney., The Journal of Histochemistry and Cytochemistry, Vol.59, No.9, 864-874, 2011.
(要約)
Focal adhesions play a critical role as centers that transduce signals by cell-matrix interactions and regulate fundamental processes such as proliferation, migration, and differentiation. Focal adhesion kinase (FAK), paxillin, integrin-linked kinase (ILK), and hydrogen peroxide-inducible clone-5 (Hic-5) are major proteins that contribute to these events. In this study, we investigated the expression of focal adhesion proteins in the developing rat kidney. Western blotting analysis revealed that the protein levels of FAK, p-FAK(397), paxillin, p-paxillin(118), and Hic-5 were high in embryonic kidneys, while ILK expression persisted from the embryonic to the mature stage. Immunohistochemistry revealed that FAK, p-FAK(397), paxillin, and p-paxillin(118) were strongly expressed in condensed mesenchymal cells and the ureteric bud. They were detected in elongating tubules and immature glomerular cells in the nephrogenic zone. Hic-5 was predominantly expressed in mesenchymal cells as well as immature glomerular endothelial and mesangial cells, suggesting that Hic-5 might be involved in mesenchymal cell development. ILK expression was similar to that of FAK in the developmental stages. Interestingly, ILK was strongly expressed in podocytes in mature glomeruli. ILK might play a role in epithelial cell differentiation as well as kidney growth and morphogenesis. In conclusion, the temporospatially regulated expression of focal adhesion proteins during kidney development might play a role in morphogenesis and cell differentiation.
Maki Urushihara : Special lecture 1 ''Intrarenal renin-angiotensin system activation in kidney development and disease'', The 4th Annual Asian Medical Conference on Child Health in Kagawa 2018, Kagawa, May 2018.
2.
Maki Urushihara, Yukiko Kinoshita, Keisuke Fujioka and Shoji Kagami : Glomerular and urinary angiotensin converting enzyme 2 in pediatric IgA nephronpathy, The 16th Korea-China-Japan Pediatric Nephrology Seminar, Apr. 2018.
3.
Keisuke Fujioka, Yukiko Kinoshita, Maki Urushihara, M Shimizu and Shoji Kagami : A case of glomerular phospholipase A receptor-positive idiopathic membranous nephropathy without deposition of complements, The 15th Japan-Korea-China Pediatric Nephrology Seminar, Apr. 2017.
4.
Maki Urushihara, T Nagai, Shuji Kondo, Toshiaki Tamaki, Yasumasa Ikeda and Shoji Kagami : (Pro)renin receptor-mediated ERK1/2 and Wnt signaling pathway in crescent glomerulonephritis., Kidney Week 2016, Nov. 2016.
5.
Yukiko Kinoshita, Keisuke Fujioka, T Nagai, N Ozaki, Maki Urushihara, Shuji Kondo and Shoji Kagami : Transition from MPGN type III to C3 glomerulonephritis in a girl with a prolonged Nephritis-associated plasmin receptor (NAPlr) deposition., 15th Asian Pacific Congress of Nephrology & 52nd Australian and New Zealand Society of Nephrology Annual Scientific Meeting, Sep. 2016.
6.
T Nagai, Maki Urushihara, Yukiko Kinoshita, Ariunbold Jamba, Shuji Kondo and Shoji Kagami : Extracellular signal regulated kinase-1/2 and -5 signaling pathways via renin angiotensin system activation play differential regulatory roles in progressive glomerulonephritis, ERA-EDTA 53rd Congress, May 2016.
7.
Maki Urushihara : Urinary angiotensinogen as a novel biomarker for intrarenal renin angiotensin system status in chornic glomerulonephritis, URINOMICS NEPHROMICS 2015, Caparica, Portugal, Sep. 2015.
8.
Shuji Kondo, A Jamba, T Nagai, Yukiko Kinoshita, Maki Urushihara and Shoji Kagami : Hic-5 Controls Mesangial Cell Proliferation in Proliferative Glomerulonephritis in Mice, 7th Europaediatrics, May 2015.
9.
T Terada, Maki Urushihara, Takahiko Saijyou, Ryuji Nakagawa and Shoji Kagami : The prorenin and soluble (pro)renin receptor may be associated with prenatal renal development in humans, 4th International CNS Germ Cell Tumor Symposium, Apr. 2015.
10.
T Nagai, T Furumoto, A Jamba, Yukiko Kinoshita, Maki Urushihara, Shuji Kondo and Shoji Kagami : The case of a 6-year-old boy with systemic lupus erythematosus complicated by membranous lupus nephritis and finger toe necrosis., XII Asian Congress of Pedatric Nephrology, Dec. 2014.
11.
T Terada, 漆原 真樹, 香美 祥二 : The prorenin and soluble (pro)renin receptor may be associated with prenatal renal development in humans., Kidney Week 2014, 2014年11月.
12.
Jamba Ariunbold, Shuji Kondo, Nagai Takashi, Maki Urushihara, Toshiaki Tamaki and Shoji Kagami : Hic-5 Regulates Mesangial Cell Proliferation via Altered and Coordinated Expression of Cell Cycle-Related Protein, American Society of Nephrology (ASN) Kidney Week 2014, Philadelphia, Nov. 2014.
13.
Maki Urushihara, Shuji Kondo, Kobori Hiroyuki, Toshiaki Tamaki and Shoji Kagami : Urinary angiotensinogen as a specific biomarker of intrarenal renin-angiotensin system status associated with glomerular injury in pediatric IgA nephropathy patients, American Society of Nephrology (ASN) Kidney Week 2014, Philadelphia, Nov. 2014.
14.
A Jamba, Shuji Kondo, Maki Urushihara, 永井 隆, J Kim-Kaneyama, A Miyazaki and Shoji Kagami : The Role of Hic-5 on Mesangial Cell Proliferation in Proliferative Glomerulonephritis in Mice., The 14th Asian Pacific Congress of Nephrology, May 2014.
15.
S Jamba, Shuji Kondo, Maki Urushihara, T Nagai, Toshiaki Tamaki and Shoji Kagami : Contribution of hydrogen peroxide-inducible clone-5 to the regulation of mesangial cell proliferation in mesangioproliferative glomerulonephritis, The annual meeting of American society of nephrology Kidney Week 2013, Nov. 2013.
16.
Keisuke Ishizawa, Noriko Yamano, Hiroyuki Kobori, Maki Urushihara, Yuki Izawa-Ishizawa, Yoshitaka Kihira, Yasumasa Ikeda, Koichiro Tsuchiya and Toshiaki Tamaki : Nitrosonifedipine prevents the progression of diabetic nephropathy via attenuating the expression of intrarenal angiotensinogen and oxidative stress, High Blood Pressure Research 2013 Scientific Sessions, Sep. 2013.
17.
Y Seki, Maki Urushihara, T Tayama, T Nagai, Yukiko Kinoshita, A Jamba, Shuji Kondo and Shoji Kagami : Glomerular ACE2 expression is enhanced in pediatric IgA nephropathy, The Sixteenth Congress of the International Pediatric Nephrology Association, Aug. 2013.
18.
T Tayama, Maki Urushihara, Y Seki, Yukiko Kinoshita, T Nagai, A Jamba, Shuji Kondo and Shoji Kagami : Effect of direct renin inhibitor on renal inflammation and (pro)renin receptor in crescentic glomerulonephritis., The Sixteenth Congress of the International Pediatric Nephrology Association, Aug. 2013.
19.
M Sato, Shuji Kondo, Yukiko Kinoshita, Ken-ichi Suga, Maki Urushihara, K Natsuko, T Nagai, Jamba Ariunbold and Shoji Kagami : Reacitve oxygen species generated by NADPH oxidase contribute to ureteric bud branching and nephrogenesis., Pediatric Academic societies annual meeting 2012, Dec. 2012.
20.
Maki Urushihara, Yukiko Kinoshita, T Nagai, Shuji Kondo, A Jamba, T Tamaki and Shoji Kagami : Effect of aliskiren on renal inflammation and (pro)renin receptor in crescentic glomerulonephritis., The American Society of Nephrology Renal Week 2012, Oct. 2012.
21.
T Nagai, Yukiko Kinoshita, S Matsuura, Ken-ichi Suga, Maki Urushihara, Shuji Kondo and Shoji Kagami : A case of membranous nephropathy with cavernous hemangioma, 11th Asian Congress of Pediatric Nephrology 2011, Jun. 2011.
22.
S Matsuura, Shuji Kondo, Ken-ichi Suga, Yukiko Kinoshita, Maki Urushihara, M Takamatsu, M Shimizu, N Kishi and Shoji Kagami : A case of membranous nephropathy and open angle glaucoma complicated with asymptomatic Sjögrens syndrome, 11th Asian Congress of Pediatric Nephrology 2011, Jun. 2011.
23.
S Matsuura, Shuji Kondo, Yukiko Kinoshita, Ken-ichi Suga, Maki Urushihara, M Takamatsu, M Shimizu, N Kishi and Shoji Kagami : The role of NADPH oxidase (Nox) in ureteric bud branching and nephrogenesis, 11th Asian Congress of Pediatric Nephrology 2011, Jun. 2011.
24.
Maki Urushihara, Yukiko Kinoshita, S Matsuura, Ken-ichi Suga, M Takamatsu, M Shimizu, Shuji Kondo, H Kobori and Shoji Kagami : Urinary angiotensinogen as a biomarker of the intrarenal status of the renin-angiotensin system in patients with chronic glomerulonephritis, 11th Asian Congress of Pediatric Nephrology 2011, Jun. 2011.
25.
Shuji Kondo, S Matsuura, Yukiko Kinoshita, Ken-ichi Suga, Maki Urushihara, T Nagai, Toshiaki Tamaki and Shoji Kagami : The expression of NADPH oxidase and reactive oxygen species (ROS) production contribute to ureteric bud branching and nephrogenesis, World Congress of Nephrology 2011, Apr. 2011.
26.
Matsuura Sato, Shuji Kondo, Ken-ichi Suga, Yukiko Kinoshita, Maki Urushihara, Toshiaki Tamaki and Shoji Kagami : Reactive oxygen species (ROS) produced by NADPH oxidase contribute ureteric bud branching and nephrogenesis, ASN 2010, Colorado, Nov. 2010.
27.
木下 ゆき子, 近藤 秀治, 須賀 健一, Sato Matsuura, 漆原 真樹, 香美 祥二 : Candesartan Suppresses Glomerular Renin-Angiotensin System (RAS) Activation, Oxidative Stress and Progressive Glomerular Injury in Rat Anti-GBM GN, The 15th Congress of the International Pediatric Nephrology Association, 2010年8月.
28.
Shuji Kondo, Ken-ichi Suga, sato Matsuura, Yukiko Kinoshita, Maki Urushihara, Toshiaki Tamaki and Shoji Kagami : Enhanced expression of Hic-5 is involved in the development of human and rat mesangioproliferative glomerulonephritis, ISN-Nexus Kyoto Symposium 2010, Apr. 2010.
29.
Maki Urushihara, Masanori Takamatsu, Maki Shimizu, Shuji Kondo, Akiko Kitamura, Yukiko Kinoshita, Keisuke Ishizawa, Toshiaki Tamaki and Shoji Kagami : The role of extracellular signal regulated kinase 5 in the accumulation of collagen matrix in rat mesangioproliferative glomerulonephritis, 40th ASN annual meeting, San Francisco, CA, Nov. 2007.
30.
Keisuke Ishizawa, Erika Miki, Arisa Hironaga, Koichiro Tsuchiya, Maki Urushihara, Shoji Kagami and Toshiaki Tamaki : Angiotensin II receptor blocker inhibits PDGF-induced cell migration in rat mesangial cells, 39th ASN annual meeting 2006, San Diego, Nov. 2006.
31.
Maki Urushihara, Masanori Takamatsu, Maki Shimizu, Shuji Kondo, Toshiaki Tamaki and Shoji Kagami : Extracellular signal regulated kinase 5 induces mesangial cell survival in rat progressive mesangioproliferative glomerulonephritis, 39th ASN annual meeting 2006, San Diego, Nov. 2006.
32.
Maki Shimizu, Shuji Kondo, Maki Urushihara, Masanori Takamatsu, Toshiaki Tamaki and Shoji Kagami : Reactive Oxygen Species (ROS) is Pivotal Mediator for Glomerular Epithelial-Mesenchymal Transition (EMT) in Experimental Progressive Glomerulonephritis (GN), 38th ASN annual meeting, Philadelphia, Nov. 2005.