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Role of catalase deficiency in progression of renal fibrosis

过氧化氢酶缺乏在肾纤维化进展中的作用

基本信息

批准号：
15590851
负责人：
SUGIYAMA Hitoshi
金额：
$ 1.98万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590851/
关键词：
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

项目摘要

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 … More 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

过氧化氢酶是调节细胞内过氧化氢和羟自由基水平的重要抗氧化酶之一。过氧化氢酶缺乏对进行性肾纤维化的影响尚未完全阐明。对纯合无过氧化氢突变小鼠（C3H/AnLCs^bCs^b）和对照野生型小鼠（C3H/AnLCs^aCs^a）进行5/6肾切除术（5/6Nx）。比较两组 5/6Nx 后 6,12 和 18 周残肾的功能和形态学变化，包括肾小管间质纤维化、上皮间质转化（EMT）、过氧化、抗氧化酶活性和 EMT 相关分子的基因表达。5/6Nx 导致白蛋白尿、肾功能下降。两组小鼠的残余肾脏中均出现 I 型和 IV 型胶原蛋白积累的功能和肾小管间质纤维化。然而，与野生型小鼠相比，5/6Nx 后这些变化的程度显着更高，直到第 18 周。通过电子显微镜在去贫血小鼠中观察到 EMT，这是肾小管上皮细胞的一个重要表型改变，并且与 EMT 相关的 □-平滑肌肌动蛋白、转化生长因子-β1、结缔组织的上调相关。生长因子和成纤维细胞特异性蛋白 1 基因表达。与野生型小鼠相比，在 5/6Nx 治疗后，去凝血酶小鼠中观察到脂质过氧化产物（包括 4-羟基-2-壬烯醛）的肾小管间质沉积和 8-羟基-2'-脱氧鸟苷的尿排泄显着增加。去贫血小鼠肾小管间质损伤后出现肾小球硬化。直到第 18 周，无过氧化氢酶小鼠残余肾脏中的过氧化氢酶活性水平仍然较低，谷胱甘肽过氧化物酶或超氧化物歧化酶 (SOD) 活性没有代偿性上调。最后，补充 SOD 模拟 tempol 并不能预防无过氧化酶残肾中的过氧化和肾小管间质纤维化。这些发现表明，无过氧化酶血症会加剧肾脏氧化组织损伤，并使残肾对 EMT 和进行性肾纤维化敏感。这项研究表明过氧化氢酶在防御氧化剂介导的肾纤维化中发挥着核心作用。较少的