title: Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis.
abstract: Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis.
  
  
  BACKGROUND
  Chronic cyclosporine (CsA) nephrotoxicity is characterized by interstitial fibrosis, tubular dropout, and loss of cellularity in areas of fibrosis. Apoptosis was found to play a role in CsA-induced fibrosis. We evaluated the role of the death genes p53, Bax, and Fas-L (ligand), survival gene Bcl-2, interleukin-converting enzyme (ICE), and caspase-3.
  
  
  METHODS
  Salt-depleted rats were administered CsA 15 mg/kg/day or vehicle (VH) and were sacrificed at 7 or 28 days. Apoptosis was detected by TdT-mediated dUTP-biotin nick end labeling assay. p53 and Bax expressions were evaluated by Northern and Western blot analysis. Fas-L and Bcl-2 expressions were evaluated by immunofluorescence. In addition to ICE mRNA, caspase-3 enzymatic activity was assayed.
  
  
  RESULTS
  Although no differences were seen at one week, apoptosis-positive cells increased with CsA at four weeks (P < 0.05) and correlated with tubular atrophy and interstitial fibrosis (r = 0.8, P < 0.05). CsA induced the expression of p53 (P < 0.05) and Bax (P < 0.01) and decreased that of Bcl-2 (P < 0.05). CsA up-regulated Fas-L expression (P < 0.001). ICE mRNA and caspase-3 activity were also increased (P < 0.01). The changes occurred as early as one week and remained statistically significant at four weeks.
  
  
  CONCLUSIONS
  Specific apoptotic genes are increased in chronic CsA nephrotoxicity. The balance favors the induction of apoptosis. Increased apoptosis could explain the tubular dropout and loss of cellularity with fibrosis. This then may impair the ability of the tubulointerstitium to remodel. Apoptosis could also contribute to some of CsA immunosuppressive effects on activated lymphocytes.
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, SaltLake City 84132, USA.
authors.forename: F S
authors.initials: FS
authors.lastname: Shihab
authors.forename: T F
authors.initials: TF
authors.lastname: Andoh
authors.forename: A M
authors.initials: AM
authors.lastname: Tanner
authors.forename: H
authors.initials: H
authors.lastname: Yi
authors.forename: W M
authors.initials: WM
authors.lastname: Bennett
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015152:Blotting, Northern; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D003404:Creatinine / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D053222:Fas Ligand Protein; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics; D015430:Weight Gain; D051028:bcl-2-Associated X Protein
chemical_list: C494828:Bax protein, rat; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D016572:Cyclosporine; D003404:Creatinine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases