Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity.
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.
Feria
Iris
I
Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico.
Pichardo
Israel
I
Juárez
Patricia
P
Ramírez
Victoria
V
González
Marco A
MA
Uribe
Norma
N
García-Torres
Romeo
R
López-Casillas
Fernando
F
Gamba
Gerardo
G
Bobadilla
Norma A
NA
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
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