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Pathologic mechanisms and therapeutic strategies to progressive renal disease by calcineurin inhibitor

钙调神经磷酸酶抑制剂治疗进展性肾病的病理机制及治疗策略

基本信息

批准号：
16590440
负责人：
MIURA Katsuyuki
金额：
$ 2.24万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590440/
关键词：
renal fibrosis nuclear factor kappaB nephrotoxicity macrophage ヘムオキシゲナーゼ NF-kappaB クルクミン

项目摘要

We previously reported that inhibition of proinflammatory transcription factor, nuclear factor kappaB (NF-κB) attenuated renal interstitial inflammation and fibrosis elicited by calcineurin inhibitors, cyclosporin A and tacrolimus. The existence of interstitial inflammatory responses are not unique to drug-induced renal fibrosis but are common to any form of renal fibrosis. Blockade of this inflammatory response led to inhibition of renal fibrosis. Oral adsorbent that inhibited intestinal absorption of uremic toxin attenuated renal NF-kB activation and inflammation that resulted in inhibition of renal fibrosis in chronic uremic model following subtotal nephrectomy. Curcumin attenuated renal inflammation and subsequently ameliorated renal fibrosis following unilateral ureteral obstruction. We showed that inhibition of NF-kB is a likely mechanism. We also showed that inhibition of enhanced expression of monocyte chemoattractant protein-1 (MCP-1) and macrophage infiltration within the kidney are possible downstream mechanisms by which these drugs acted.As Rho-kinase play a role in inflammation, we next elucidated the role of Rho-kinase in renal inflammation and fibrosis elicited by two different maneuver, tacrolimus administration and ureteral occlusion. Rho-kinase inhibitor, fasudil partially attenuated renal inflammation following ureteral occlusion but not that observed in chronic tacrolimus nephrotoxicity. These results may indicate that Rho-kinase is not a common mechanism by which renal fibrosis develops. Further study is required to clarify the precise role of Rho-kinase in the pathogenesis of renal fibrosis.

我们先前报道了抑制促炎转录因子核因子κ B（NF-κB）可减轻钙调磷酸酶抑制剂环孢菌素A和他克莫司引起的肾间质炎症和纤维化。间质炎症反应的存在并非药物诱导的肾纤维化所独有，而是任何形式的肾纤维化所共有的。这种炎症反应的阻断导致肾纤维化的抑制。抑制尿毒症毒素肠吸收的口服吸附剂减弱了肾NF-κ B活化和炎症，导致慢性尿毒症模型肾次全切除术后肾纤维化抑制。姜黄素减轻肾脏炎症，随后改善单侧输尿管梗阻后的肾纤维化。我们发现NF-kB的抑制是一种可能的机制。由于Rho激酶在炎症反应中起重要作用，我们进一步阐明了Rho激酶在他克莫司给药和输尿管阻断两种不同方法引起的肾脏炎症和纤维化中的作用。Rho激酶抑制剂法舒地尔部分减轻输尿管闭塞后的肾脏炎症，但在慢性他克莫司肾毒性中未观察到。这些结果可能表明Rho激酶不是肾纤维化发展的常见机制。Rho激酶在肾纤维化发病机制中的确切作用有待进一步研究。