title: 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.
abstract: 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.
authors.affiliation: Division of Nephrology, Staten Island University Hospital, Staten Island, New York, USA.
authors.forename: Subodh J
authors.initials: SJ
authors.lastname: Saggi
authors.forename: Takeshi F
authors.initials: TF
authors.lastname: Andoh
authors.forename: Robert
authors.initials: R
authors.lastname: Safirstein
authors.forename: William M
authors.initials: WM
authors.lastname: Bennett
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D004247:DNA; D014700:Verapamil