| Research Abstract |
(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
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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
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