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

虽然环孢素（CsA）是一种有效的和选择性的免疫抑制剂，其充分的临床使用有时已被限制其肾毒性。本研究旨在阐明CsA肾毒性的可能机制，特别是肾小管间质纤维化（TIF）的发病机制。我们使用实验性大鼠模型的慢性CsA肾毒性和检查CsA对肾功能，组织学和基因表达的促纤维化分子和细胞外基质的时程效应。我们首先发现，通过口服镁（Mg）补充剂纠正CsA诱导的低镁血症可通过抑制促纤维化分子预防TIF。镁还阻断与巨噬细胞内流和巨噬细胞趋化因子、骨桥蛋白和MCP-1的基因表达相关的早期间质炎症。提示Mg抑制趋化因子的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，阻断激活的转录因子，NFkB的镁参与机制，镁补充衰减CsA诱导的TIF。镁的大部分治疗作用似乎不依赖于肾素-血管紧张素系统。

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.