| Project/Area Number |
15590851
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Okayama University |
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Principal Investigator |
SUGIYAMA Hitoshi Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Department of Medicine and Clinical Science, Assistant Professor, 大学院・医歯薬学総合研究科, 助手 (60325090)
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| Co-Investigator(Kenkyū-buntansha) |
WANG Dahong Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Department of Medicine and Clinical Science, Assistant Professor, 大学院・医歯薬学総合研究科, 助手 (90294404)
MAESHIMA Yohei Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Department of Medicine and Clinical Science, Assistant Professor, 大学院・医歯薬学総合研究科, 助手 (10343287)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | acatalasemia / acatalasemic mice / catalase / reactive oxygen species / oxidative stress / epithelial to mesenchymal transition / renal interstitial fibrosis / 5 / 6 nephrectomy / フリーラジカル / アポトーシス / 尿細管上皮細胞 / 腎間質線維症 / 腎臓内科学 |
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| Research Abstract |
Catalase is one of the important antioxidant enzymes regulating the levels of intracellular hydrogen peroxide and hydroxyl radical. The effect of catalase deficiency on progressive renal fibrosis has not been fully elucidated yet.
Homozygous acatalasemic mutant mice (C3H/AnLCs^bCs^b) and control wild-type mice (C3H/AnLCs^aCs^a) were subjected to 5/6 nephrectomy (5/6Nx). The functional and morphological alterations of the remnant kidneys including tubulointerstitial fibrosis, epithelial to mesenchymal transition (EMT), peroxidation, antioxidant enzyme activity and gene expression of EMT-related molecules were compared between the two groups at 6,12, and 18 wk after 5/6Nx.
The 5/6Nx resulted in albuminuria, decreased renal function, and tubulointerstitial fibrosis with accumulation of type I and type IV collagens in the remnant kidneys of both mouse groups. However, the degree of these changes was significantly higher in acatalasemic mice after 5/6Nx as compared with wild-type mice until w
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eek 18. EMT, a crucial phenotypic alteration of tubular epithelial cells was observed in acatalasemic mice by electron microscopy and was associated with upregulation of EMT-related □-smooth muscle actin, transforming growth factor-β1, connective tissue growth factor, and fibroblast specific protein-1 gene expression. Significant increases in the tubulointerstitial deposition of lipid peroxidation products including 4-hydroxy-2-nonenal and urinary excretion of 8-hydroxy-2'- deoxyguanosine were observed in the acatalasemic mice after 5/6Nx as compared with the wild-type mice. Glomerular sclerosis developed after tubulointerstitial injury in acatalasemic mice. The level of catalase activity remained low in the remnant kidneys of acatalasemic mice until week 18 without compensatory upregulation of glutathione peroxidase or superoxide dismutase (SOD) activity. Finally, supplementation of a SOD mimetic tempol did not prevent peroxidation and tubulointerstitial fibrosis in the acatalasemic remnant kidneys.
These findings indicate that acatalasemia exacerbates renal oxidant tissue injury and sensitizes remnant kidneys to EMT and progressive renal fibrosis. This study suggests a central role for catalase in the defense against oxidant-mediated renal fibrosis. Less
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