Role of catalase deficiency in progression of renal fibrosis

过氧化氢酶是调节细胞内过氧化氢和羟基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。纯合子无血突变小鼠（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）。在5/6Nx后6、12和18周，比较两组残肾的功能和形态学改变，包括小管间质纤维化、上皮向间质转化（EMT）、过氧化、抗氧化酶活性和EMT相关分子的基因表达。5/6Nx导致两组小鼠残肾出现蛋白尿、肾功能下降和小管间质纤维化，并伴有I型和IV型胶原的积累。然而，与野生型小鼠相比，在5/6Nx后，这些变化的程度明显高于野生型小鼠，直到第18周。电镜观察发现，EMT是致凝血小鼠小管上皮细胞的一个重要表型改变，并与EMT相关的□-平滑肌肌动蛋白、转化生长因子-β1、结缔组织生长因子和成纤维细胞特异性蛋白-1基因表达上调有关。与野生型小鼠相比，5/6Nx后，无血凝血小鼠的脂质过氧化产物（包括4-羟基-2-壬烯醛）的管间沉积和尿中8-羟基-2'-脱氧鸟苷的排泄显著增加。致凝血小鼠肾小管间质损伤后发生肾小球硬化。未见谷胱甘肽过氧化物酶或超氧化物歧化酶（SOD）活性代偿性上调。最后，补充一种模拟SOD的tempol并不能防止缺血残肾的过氧化和小管间质纤维化。这些结果表明，阿卡塔血症加重了肾氧化性组织损伤，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抗氧化介导的肾纤维化中的核心作用。少

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