title: Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity.
abstract: BACKGROUND
  Cyclosporine A (CsA) is an immunosuppressive drug used to prevent tissue allograft rejection. However, its long-term utilization is limited due to chronic nephrotoxicity for which no prevention is available. This study evaluated the effect of spironolactone on renal functional and structural alterations induced by CsA, and assessed whether the protective effect was associated with a reduction of transforming growth factor-beta (TGF-beta) and the change of extracellular matrix protein mRNA level.
  
  
  METHODS
  Male Wistar rats fed with low sodium diet were divided in four treatment groups: vehicle, CsA (30 mg/kg), spironolactone (20 mg/kg), or CsA+spironolactone. After 21 days, creatinine clearance (CCr), blood CsA, arteriolopathy in renal tissue, and TGF-beta, collagen I, collagen IV, fibronectin, and epidermal growth factor (EGF) mRNA levels in renal cortex were determined.
  
  
  RESULTS
  CsA reduced the CCr and up-regulated TGF-beta, collagen I and fibronectin mRNA expression with a significant development of arteriolopathy, and reduced EGF mRNA levels. In contrast, spironolactone administration prevented the fall in renal function and TGF-beta, collagen I, and fibronectin up-regulation, together with a reduction of arteriolopathy and tubulointerstitial fibrosis.
  
  
  CONCLUSIONS
  Our data show that aldosterone plays an important role as a mediator of renal injury induced by CsA. Thus, mineralocorticoid receptor blockade may be a potential strategy to prevent CsA nephrotoxicity.
authors.affiliation: Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico.
authors.forename: Iris
authors.initials: I
authors.lastname: Feria
authors.forename: Israel
authors.initials: I
authors.lastname: Pichardo
authors.forename: Patricia
authors.initials: P
authors.lastname: Juárez
authors.forename: Victoria
authors.initials: V
authors.lastname: Ramírez
authors.forename: Marco A
authors.initials: MA
authors.lastname: González
authors.forename: Norma
authors.initials: N
authors.lastname: Uribe
authors.forename: Romeo
authors.initials: R
authors.lastname: García-Torres
authors.forename: Fernando
authors.initials: F
authors.lastname: López-Casillas
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
authors.forename: Norma A
authors.initials: NA
authors.lastname: Bobadilla
mesh_terms: D000450:Aldosterone / Q000502:physiology; D000818:Animals; D002908:Chronic Disease; D024042:Collagen Type I / Q000235:genetics; D024141:Collagen Type IV / Q000235:genetics; D016572:Cyclosporine / Q000633:toxicity*; D005353:Fibronectins / Q000235:genetics; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D024042:Collagen Type I; D024141:Collagen Type IV; D005353:Fibronectins; D007166:Immunosuppressive Agents; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013148:Spironolactone; D000450:Aldosterone; D016572:Cyclosporine