Study on pathogenesis of renal interstitial fibrosis by an immunosuppressant, cyclosporine A

免疫抑制剂环孢素A致肾间质纤维化发病机制的研究

• 批准号: 11672272
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672272/
• 关键词: cyclosporine A; renal fibrosis; nephrotoxicity

Although cyclosporine (CsA) is a potent and selective immunosuppressive agent, its full clinical use has been sometimes limited by its nephrotoxicity. The present research project was conducted to elucidate the possible mechanism of CsA nephrotoxicity, particularly pathogenesis of tubulo-interstitial fibrosis (TIF). We used experimental rat model of chronic CsA nephrotoxicity and examined time course effects of CsA on renal function, histology and gene expression of pro-fibrogenic molecules and extracellular matrices. We first found that correction of CsA-induced hypomagnesemia by oral magnesium (Mg) supplementation prevented TIF through inhibition of pro-fibrogenic molecules. Mg also blocked early interstitial inflammation associated with macrophage influx and gene expression of macrophage chemoattractants, osteopontin and MCP-1. It was suggested that inhibition of chemoattractants expression by Mg resulted in blockade of macrophage influx and interstitial inflammation, thereby prevented TIF. Furthermore, we demonstrated that blockade of activation of a transcription factor, NFkB by Mg was involved in the mechanisms by which Mg supplementation attenuated CsA-induced TIF. Most of the therapeutic effects of Mg appear to be independent of renin-angiotensin system.

虽然环孢素（CsA）是一种有效的选择性免疫抑制剂，但其临床应用有时因其肾毒性而受到限制。本研究旨在阐明CsA肾毒性的可能机制，特别是小管间质纤维化（TIF）的发病机制。采用慢性CsA肾毒性大鼠实验模型，观察CsA对肾脏功能、促纤维化分子和细胞外基质的组织学和基因表达的时间过程影响。我们首先发现，口服镁（Mg）补充剂通过抑制促纤维化分子来纠正csa诱导的低镁血症。Mg还阻断与巨噬细胞内流相关的早期间质炎症，以及巨噬细胞趋化剂、骨桥蛋白和MCP-1的基因表达。提示Mg抑制趋化剂表达可阻断巨噬细胞内流和间质炎症，从而预防TIF。此外，我们证明了Mg对转录因子NFkB激活的阻断参与了Mg补充减轻csa诱导的TIF的机制。Mg的大多数治疗作用似乎与肾素-血管紧张素系统无关。

项目成果

K.Miura et al.: "Role of hypomagnesemia in chronic cyclosporine nephropathy"Transplantation. 73. 340-347 (2002)

K.Miura 等人：“低镁血症在慢性环孢素肾病中的作用”移植。

K.Miura et al.: "Effects of nitric oxide scavenger, carboxy-PTIO on endotoxin-induced alterations in systemic hemodynamics in rats"Jpn J Pharmacol. 82. 261-264 (2000)

K.Miura 等：“一氧化氮清除剂羧基-PTIO 对内毒素诱导的大鼠全身血流动力学改变的影响”Jpn J Pharmacol。

Miura, K. et al.: "Role of hypomagnesemia in chronic cyclosporine nephropathy"Transplantation. 73. 340-347 (2002)

Miura, K. 等人：“低镁血症在慢性环孢素肾病中的作用”移植。

T.Nakatani et al.: "Effect of tacrolimus on the gene expression of renin and endothelin in the rat kidney"Transplant Proc. 33. 2296-2297 (2001)

T.Nakatani 等：“他克莫司对大鼠肾脏肾素和内皮素基因表达的影响”Transplant Proc。

T.Nakatani et al.: "Effect of facrolimus on the gene expression of renin and endothelin in the rat kidney"Transplant Proc. 33. 2296-2297 (2001)

T.Nakatani 等人：“法罗莫司对大鼠肾脏肾素和内皮素基因表达的影响”移植程序。