NDT Advance Access published online on April 18, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn204
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Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats
1 Institute of Physiology and Pharmacology, University of Southern Denmark 2 Department of Nephrology, Odense University Hospital 3 Institute of Pathology, University of Southern Denmark, Odense, Denmark
Correspondence and offprint requests to: Finn Thomsen Nielsen, Institute of Physiology and Pharmacology, University of Southern Denmark, Winsløwparken 21, 3, DK-5000 Odense C, Denmark. Tel: +45-2443-4346; Fax: +45-6541-3452; E-mail: ftn{at}dadlnet.dk
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Abstract |
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Background. Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats.
Methods. Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats.
Results. CsA significantly increased systolic BP: 139 ± 4 versus 134 ± 2 mmHg, reduced body weight gain: –5 ± 6 versus 36 ± 7 g, glomerular filtration rate (GFR): 1.02 ± 0.16 versus 2.64 ± 0.27 ml/min, renal blood flow (RBF): 5.3 ± 2.4 versus 13.5 ± 2.1 ml/min and lithium clearance (CLi+): 0.16 ± 0.04 versus 0.26 ± 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 ± 4 mmHg; weight gain, 53 ± 7 g; GFR, 1.67 ± 0.26 ml/min; RBF, 12.3 ± 2.1 ml/min and CLi+, 0.27 ± 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality.
Conclusions. MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.
Keywords: cyclosporin A; eplerenone; glomerular filtration rate; mineralocorticoid receptor antagonist; nephrotoxicity
Received for publication: 8. 6.07
Accepted in revised form: 19. 3.08