Cyclosporin induces renal proto-oncogene RNA message and increased transforming growth factor-β prior to renal fibrosis:: Modification by calcium channel blockade in the salt replete rat

Background: Chronic cyclosporin (CsA) administration has been shown to result in the replacement of epithelial cells in the kidney with fibrous tissue. These changes are kidney-specific, as they do not occur in any other organ. Results: Cyclosporin exposure increases c-fos and c-jun mRNA in the rat kidney but not in the liver. Furthermore, chronic CsA exposure causes a further increase in c-fos and c-jun mRNA and increases the renal expression of transforming growth factor-beta (TGF-beta) mRNA. These changes precede the development of fibrosis. The combined insult of ischaemia and CsA resulted in synergistic increases in c-fos, suggesting that CsA recruited a pathway for c-fos activation different from ischaemia. The calcium channel blocker, verapamil, blocked CsA-induced expression of c-fos and c-jun mRNA, and reduced the amount of TGF-beta expression. Conclusion: These data are consistent with the notion that CsA induces protooncogenes, which may be, at least partially, responsible for long-term CsA nephrotoxicity.