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).
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, 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.
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.
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.