Molecular mechanisms of ischemia/reperfusion-induced renal injury

缺血/再灌注肾损伤的分子机制

基本信息

批准号：
14570092
负责人：
MATSUMURA Yasuo
金额：
$ 2.24万
依托单位：
Osaka University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

(1) : To investigate the role of Rho-kinase in the pathogenesis of ischemic acute renal failure (ARF), we examined the effect of Y-27632, a selective Rho-kinase inhibitor, on the ischemia/reperfusion-induced ARF. Y-27632 markedly suppressed the development of ischemia/reperfusion (I/R)-induced ARF and the effects was related to the suppression of neutrophil infiltration, thereby suggesting that the Rho/Rho-kinase pathway plays a key role in the pathogenesis of ischemic ARE.(2) : We evaluated the effects of SEA0400, a novel and selective Na^+/Ca^<2+> exchange (NCX) inhibitor, on ischemic ARF SEA0400 dose-dependently attenuated the I/R-induced renal dysfunction and histological damage. Next, using NCX^<+/-> heterozygous mice, the pathophysiological role of Ca^<2+> overload via the reverse mode of NCX in I/R-induced renal injury, was investigated. I/R-induced renal dysfunction in heterozygous mice were significantly attenuated compared with cases in wild-type mice. Histological renal dama … More ge in heterozygous mice was much less than that in wild-type mice. Increases in renal endothelin-1 content were greater in wild-type than in heterozygous mice. These findings strongly support the view that Ca^<2+> overload via the reverse-mode of NCX, followed by renal endothelin-1 overproduction, plays an important role in the pathogenesis of I/R-induced renal injury. In addition, the possibility exists that a selective NCX inhibitor such as SEA0400 is useful as effective therapeutic agent against ischemic ARF.(3): Effects of nitric oxide (NO) donor, FK409, on the I/R-induced ARE were investigated. The pre-ischemic treatment with FK409 markedly suppressed the renal lesion by the antioxidative action and decreasing endothelin-1 production. In contrast, the post-ischemic treatment with FK409 aggravated the I/R-induced renal dysfunction and histological damage. Immunohistochemical analysis of renal sections obtained from ARE rats revealed positive staining for nitrotyrosine, a biomarker of peroxynitrite formation, in injured tubular cells, and more intense staining was observed in renal tissues from animals received post-ischemic treatment with FK409. These results demonstrate that, although pre-ischemic treatment with NO donor is renoprotective, post-ischemic treatment with the same agent aggravates the I/R-induced renal injury, probably through the peroxynitrite overproduction. Less

(1)：为了研究 Rho 激酶在缺血性急性肾衰竭 (ARF) 发病机制中的作用，我们检测了选择性 Rho 激酶抑制剂 Y-27632 对缺血/再灌注诱导的 ARF 的作用。 27632 显着抑制了缺血/再灌注 (I/R) 的发生，从而诱导了 ARF，并且该作用与抑制中性粒细胞浸润有关，表明Rho/Rho 激酶通路在缺血性 ARE 的发病机制中起着关键作用。(2)：我们评估了 SEA0400（一种新型选择性 Na^+/Ca^2+> 交换 (NCX) 抑制剂）对缺血性 ARE 的影响。缺血性 ARF SEA0400 剂量依赖性地减轻 I/R 诱导的肾功能障碍和组织学损伤。研究发现，与野生型小鼠相比，杂合小鼠中I/R诱导的肾功能障碍中Ca 2+ 超载通过NCX的反向模式显着减弱。杂合子小鼠的肾损伤比强野生型小鼠的肾内皮素-1 含量增加得多，这些发现支持这样的观点：通过NCX的反向模式导致的Ca 2+ 超载以及随后的肾内皮素-1过量产生，在I/R诱导的肾损伤的发病机制中起重要作用。此外，存在选择性NCX抑制剂的可能性。例如SEA0400可用作针对缺血性ARF的有效治疗剂。(3)：研究了一氧化氮(NO)供体FK409对I/R诱导的ARE的影响。 FK409 的缺血前治疗通过抗氧化作用和减少内皮素-1 的产生显着抑制了肾脏病变，相反，FK409 的缺血后治疗加剧了缺血再灌注引起的肾功能障碍和肾切片的组织学损伤。从 ARE 大鼠身上获得的结果显示，在受损的肾小管细胞中硝基酪氨酸（一种过氧亚硝酸盐形成的生物标志物）呈阳性染色，并且观察到更强烈的染色在接受 FK409 缺血后治疗的动物的肾组织中，这些结果表明，尽管使用 NO 供体进行缺血前治疗具有肾脏保护作用，但使用相同药物进行缺血后治疗可能会通过过氧亚硝酸盐过量产生较少。