The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity

Background: Chronic cyclosporine-(CsA)-mediated loss of kidney function is a major clinical problem in organ transplantation. We hypothesized that the mineralocorticoid receptor antagonist eplerenone (EPL) prevents chronic CsA-induced renal interstitial volume increase, tubule loss, and functional impairment in a rat model. Methods: Sprague-Dawley rats received CsA alone (15 mg/kg/d p.o.), CsA and EPL (approximately 100 mg/kg/day p.o.) or vehicle (control) for 12 weeks. At 11 weeks, chronic indwelling arterial and venous catheters were implanted for continuous measurements of arterial blood pressure (BP) and GFR (inulin clearance) in conscious, freely moving animals. Plasma was sampled for analysis and kidney tissue was fixed for quantitative stereological analyses. Results: Compared to controls, CsA-treatment reduced relative tubular volume (0.73 +/- 0.03 vs. 0.85 +/- 0.01, p<0.05) and increased relative interstitial volume (0.080 +/- 0.004 vs. 0.045 +/- 0.003, p<0.05); EPL attenuated these changes (0.82 +/- 0.02, p<0.05, and 0.060 +/- 0.006, p<0.05, respectively). CsA-treated rats had more sclerotic glomeruli and a higher degree of vascular depositions in arterioles; both were significantly reduced in CsA+EPL-treated animals. CsA increased BP and reduced body weight gain and GFR. In CsA+ EPL rats, weight gain, GFR and BP at rest (daytime) were normalized; however, BP during activity (night) remained elevated. Plasma sodium and potassium concentrations, kidney-to-body weight ratios and CsA whole blood concentration were similar in CsA and CsA+ EPL rats. Conclusions: It is concluded that in the chronic cyclosporine rat nephropathy model, EPL reduces renal tissue injury, hypofiltration, hypertension, and growth impairment. MR antagonists should be tested for their renoprotective potential in patients treated with calcineurin inhibitors.