Cyclosporin induces renal proto-oncogene RNA message and increased transforming growth factor-beta 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.


CONCLUSIONS
These data are consistent with the notion that CsA induces protooncogenes, which may be, at least partially, responsible for long-term CsA nephrotoxicity.
Saggi
Subodh J
SJ
Division of Nephrology, Staten Island University Hospital, Staten Island, New York, USA.
Andoh
Takeshi F
TF
Safirstein
Robert
R
Bennett
William M
WM
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis; D053938:DNA Fragmentation; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D014700:Verapamil / Q000494:pharmacology
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D004247:DNA; D014700:Verapamil