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

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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.