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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
Author(s) -
SAGGI SUBODH J,
ANDOH TAKESHI F,
SAFIRSTEIN ROBERT,
BENNETT WILLIAM M
Publication year - 2004
Publication title -
nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 61
eISSN - 1440-1797
pISSN - 1320-5358
DOI - 10.1111/j.1440-1797.2003.00230.x
Subject(s) - medicine , blockade , calcium channel , fibrosis , oncogene , rna , cancer research , transforming growth factor , calcium , receptor , biochemistry , biology , cell cycle , cancer , gene
SUMMARY: 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‐β (TGF‐β) 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‐β 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.