Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats
Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats
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DOI：
10.1097/01.asn.0000074239.22357.06
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发表时间：
2003-07-01
影响因子：
13.6
通讯作者：
Nangaku, M
中科院分区：
文献类型：
--
作者：
Matsumoto, M;Makino, Y;Nangaku, M
肾小管上皮细胞的缺氧被认为在急性肾衰竭的病理生理学和慢性肾脏疾病的进展中起关键作用。预诱导缺氧诱导和肾保护基因表达可保护随后的缺血损伤。本研究评价了钴在大鼠急性缺血性肾小管间质损伤模型中抑制HIF-1降解和增加缺氧相关基因表达水平的功效。通过夹闭肾蒂45分钟并切除对侧肾造成缺血性肾损伤。观察缺血损伤后血清肌酐升高和形态学损伤。给予氯化钴可显著改善功能（平均+/- SEM肌酐，mg/dl：钴治疗组，2.14 +/- 1.21;对照组，3.69 +/- 1.43; P < 0.05），并改善肾小管间质损伤。钴处理还显著减少巨噬细胞浸润。在用钴处理的大鼠的肾脏中，用于组织保护的几个基因的mRNA水平在缺血性损伤之前增加，例如HO-1、EPO、Glut-1和VEGF。在蛋白质水平证实了钴对HO-1的上调。皮下注射钴也能改善缺血性损伤，这与肾HIF-1 α蛋白表达上调有关。这些结果表明，对缺氧肾小管间质损伤的保护钴管理介导的诱导肾保护基因的表达。HIF诱导是一个可能的和有吸引力的解释所观察到的效果。
Hypoxia in the tubulointerstitium has been thought to play pivotal roles in the pathophysiology of acute renal failure and the progression of chronic kidney disease. Pre-induction of hypoxia-inducible and renoprotective gene expression may protect subsequent ischemic injury. This study evaluated the efficacy of cobalt, which inhibits HIF-1 degradation and increases the expression level of hypoxia-related genes, in an acute ischemic tubulointerstitial injury model of rats. Ischemic renal injury was induced by 45-min clamping of renal pedicles with contralateral nephrectomy. Elevation of serum creatinine and morphologic injury after the ischemic insult was observed. Administration of cobalt chloride afforded striking functional improvement (mean +/- SEM creatinine in mg/dl: Co treatment group, 2.14 +/- 1.21; control, 3.69 +/- 1.43; P < 0.05) associated with amelioration of tubulointerstitial damage. Cobalt treatment also reduced macrophage infiltration significantly. In the kidney of rats treated with cobalt, mRNA levels of several genes that serve for tissue protection, such as HO-1, EPO, Glut-1, and VEGF, were increased before ischemic injury. Upregulation of HO-1 by cobalt was confirmed at the protein level. Subcutaneous injection of cobalt also ameliorated ischemic injury, which was associated with upregulation of renal HIF-1alpha protein expression. These results suggest that protection against hypoxic tubulointerstitial injury by cobalt administration is mediated by induction of renoprotective gene expression. HIF induction is one possible and attractive explanation for the observed effects.