Molecular mechanisms of ischemia/reperfusion-induced renal injury

缺血/再灌注肾损伤的分子机制

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570092/
• 关键词: kidney; ischemia; acute renal failure; Na^+; Ca^<2+> exchanger; nitric oxide; peroxynitrite; Rho-kinase; endothelin-1; 酸化ストレス; 活性酸素; NOドナー; ニトロチロシン; Na^+; Ca^<2+>交換体; Rho-kinase

(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)：为了探讨rho激酶在缺血性急性肾功能衰竭（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的影响。Y-27632明显抑制缺血再灌注（I/R）诱导的ARF的发生，其作用与抑制中性粒细胞浸润有关，提示Rho/Rho激酶通路在缺血性ARE发病机制中起关键作用。(2)：我们评估了新型选择性Na^+/Ca^<2+>交换（NCX）抑制剂SEA0400对缺血性ARF的作用，SEA0400剂量依赖性地减轻了I/ r诱导的肾功能障碍和组织学损害。接下来，我们利用NCX^< 2+ /->杂合小鼠，通过NCX的反向模式研究Ca^<2+>过载在I/ r诱导的肾损伤中的病理生理作用。与野生型小鼠相比，杂合小鼠I/ r诱导的肾功能障碍明显减弱。杂合子小鼠肾组织损伤明显小于野生型小鼠。野生型小鼠肾内皮素-1含量的增加高于杂合型小鼠。这些发现有力地支持了Ca^<2+>通过NCX的反向模式过载，随后是肾内皮素-1的过量产生，在I/ r诱导的肾损伤的发病机制中起重要作用的观点。此外，SEA0400等选择性NCX抑制剂有可能作为缺血性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缺血前处理通过抗氧化作用和降低内皮素-1的产生显著抑制肾损害。相反，缺血后用FK409治疗加重了I/ r诱导的肾功能障碍和组织学损害。免疫组织化学分析ARE大鼠肾切片显示，损伤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，FK409缺血后的动物肾组织中染色更强烈。这些结果表明，尽管用NO供体进行缺血前治疗具有肾保护作用，但用相同的药物进行缺血后治疗可能会加重I/ r诱导的肾损伤，这可能是通过过氧亚硝酸盐过量产生的。少

项目成果

Junzi Yamashita: "Role of nitric oxide in the renal protective effects of ischemic preconditioning"J.Cardiovasc.Pharmacol.. 42・3. 419-427 (2003)

Junzi Yamashita：“一氧化氮在缺血预处理的肾脏保护作用中的作用”J.Cardiovasc.Pharmacol.. 42・3（2003）。

Masaya Ogata: "A novel and selective Na^+/Ca^<2+> exchange inhibitor, SEA0400, improves ischemia/reperfusion-induced renal injury"Eur.J.Pharmacol.. 478. 187-198 (2003)

Masaya Ogata：“一种新颖且选择性的Na ^ /Ca ^ 2 交换抑制剂，SEA0400，改善缺血/再灌注诱导的肾损伤”Eur.J.Pharmacol.. 478. 187-198 (2003)

Masanori Takaoka: "Pathophysiological role of proteasome-dependent proteolytic pathway in endothelin-1-related cardiovascular diseases"Current Vascular Pharmacology. 1. 19-26 (2003)

Masanori Takaoka：“蛋白酶体依赖性蛋白水解途径在内皮素-1相关心血管疾病中的病理生理作用”当前血管药理学。

Dietary supplementation of L-carnosine prevents ischemia/reperfusion-induced renal injury in rats.

• 发表时间: 2005-02
• 期刊: Biological & pharmaceutical bulletin
• 影响因子: 2
• 作者: T. Fujii;M. Takaoka;N. Tsuruoka;Y. Kiso;Takaharu Tanaka;Y. Matsumura

Preventive effect of L-carnosine on ischaemia/reperfusion-induced acute renal failure in rats

L-肌肽对大鼠缺血/再灌注急性肾衰竭的预防作用

• 发表时间: 2003
• 期刊: Eur J.Pharmacol. 474
• 作者: Fukushima;Y.;Nagayama;T.;Hikichi;H.;Mizukami;K.;Yoshida;M.;Suzuki-Kusaba;M.;Hisa;H.;Kimura;T.;Satoh;S.;Toshihide FUJII
• 通讯作者: Toshihide FUJII