NDT Advance Access published online on August 8, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp371
Increased renoprotection with ACE inhibitor plus aldosterone antagonist as compared to monotherapies—the effect on podocytes
1 Department of Pathophysiology, Semmelweis University, Budapest, Hungary 2 Institute of Pathology 3 Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany
Correspondence and offprint requests to: Péter Hamar; E-mail: hampet{at}net.sote.hu
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Abstract |
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Background. Blockade of the renin–angiotensin–aldosterone system (RAAS) does not completely prevent progression of renal disease. Mineralocorticoid receptor blockade provides additional renoprotection over ACE-inhibition monotherapy. We examined the mechanisms underlying superior renoprotection in the subtotal nephrectomy (SNX) model.
Methods. Sprague-Dawley rats were randomized into six groups: (1) sham-op, (2) SNX without treatment, (3) SNX + quinapril (Q), (4) SNX + spironolactone (S), (5) SNX + combination therapy (Q+S), (6) SNX + combination hydrochlorothiazide + reserpin + hydralazine (HRH). Albuminuria and blood pressure were monitored, and kidneys were examined by morphometric and molecular methods.
Results. In SNX rats, albumin excretion was significantly higher than in sham-op rats. Blood pressure reduction was not significantly different between the treatment groups. All therapies (S, Q, Q+S and HRH) reduced albuminuria; the values were lowest in animals treated with Q+S. The volume density of glomerular matrix and the number of mesangial cells were significantly increased in SNX and were lowest in SNX treated with Q+S. The number of podocytes was reduced in SNX, but was normalized in SNX treated with Q+S. Glomerular volumes and podocyte volumes were significantly higher in SNX than in sham-op. Both volumes were reduced by all interventions, but almost normalized by treatment with Q+S. Expression of collagen IV, TGF-β1 and desmin was increased after SNX and significantly reduced by treatment with Q and Q+S.
Conclusions. In subtotally nephrectomized rats, mineralocorticoid blockade provided additional renoprotection over and above ACE inhibition. Such benefit was paralleled by major changes in podocyte number and morphology and was not blood pressure dependent.
Keywords: aldosterone; chronic kidney failure; progression of chronic renal failure; renin–angiotensin system
* The first two authors contributed equally to this work.
Received for publication: 9. 2.09
Accepted in revised form: 6. 7.09