title: Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity.
abstract: OBJECTIVE
  The fact that mineralocorticoid receptor antagonists reduce structural and functional alterations induced by cyclosporine A (CsA) indicates that aldosterone plays a key role in chronic CsA nephrotoxicity. We and other researchers have reported local renal aldosterone synthesis. To investigate local renal aldosterone's role in chronic CsA nephrotoxicity, we evaluated the effect of eplerenone (Epl) on renal structural damage and renal dysfunction in adrenalectomized (ADX) rats, and assessed whether the therapeutic benefit was associated with reduction of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), plasminogen activator inhibitor type 1 (PAI-1) and collagen I (COL-I) expression.
  
  
  METHODS
  Male Sprague-Dawley rats fed a normal-sodium diet were divided in four groups: sham-ADX, ADX, CsA, or Epl. Rats in the ADX, CsA and Epl groups were adrenalectomized first. Aldosterone, sodium and potassium levels in serum and urine were measured on the second day. Two weeks later, vehicle (sham-ADX and ADX group), CsA (25mg/kg/d), or CsA and Epl (100 mg/ kg/d) combination was administrated, respectively. After six weeks, urinary protein, creatinine clearance (Ccr), tubulointerstitial fibrosis (TIF), aldosterone level in kidney, and renal aldosterone synthase CYP11B2, COL-I, TGF-β1, CTGF and PAI-1 gene expression levels were determined.
  
  
  RESULTS
  On the second day after surgery, adrenalectomized rats showed undetectable aldosterone with natriuresis, hyponatremia, decreased urinary potassium excretion and hyperpotassemia. CsA reduced Ccr, induced urinary proteins and up-regulated COL-I, TGF-β1, CTGF and PAI-1 gene expression with a significant development of TIF. Eplerenone administration prevented TIF and COL-I, TGF-β1 and PAI-1 up-regulation but did not improve renal function.
  
  
  CONCLUSIONS
  Our results suggest local renal aldosterone is an important mediator of renal injury induced by CsA.
authors.affiliation: Department of Nephrology, Qilu Hospital, Shandong University, China.
authors.forename: Qiao-Ling
authors.initials: QL
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Qianfoshan Hospital, Shandong University, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Nephrology, Beijing An Zhen Hospital, Capital Medical University, China.
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Rui
authors.affiliation: Department of Nephrology, Beijing An Zhen Hospital, Capital Medical University, China yipuchen1980@163.com.
authors.forename: Yi-Pu
authors.initials: YP
authors.lastname: Chen
mesh_terms: D000315:Adrenalectomy; D000450:Aldosterone / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000009:adverse effects*; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004573:Electrolytes / Q000097:blood / Q000652:urine; D000077545:Eplerenone; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology / Q000652:urine; D008297:Male; D011188:Potassium / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004573:Electrolytes; D012333:RNA, Messenger; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D016572:Cyclosporine; D012964:Sodium; D019405:Cytochrome P-450 CYP11B2; D011188:Potassium
keywords: Aldosterone; calcineurin inhibitor; cyclosporine; mineralocorticoid receptor antagonist; nephrotoxicity; tubulointerstitial fibrosis