Effect of a novel nonsteroidal selective mineralocorticoid receptor antagonist, esaxerenone (CS-3150), on blood pressure and renal injury in high salt-treated type 2 diabetic mice.

Abstract

Although beneficial antihypertensive and antialbuminuric effects of steroidal mineralocorticoid receptor (MR) antagonists have been shown, the use of these drugs has been clinically limited in diabetic kidney disease (DKD) because of the high incidence of side effects. Here, we aimed to examine the effect of a novel nonsteroidal selective mineralocorticoid receptor antagonist, esaxerenone, on blood pressure and renal injury in high salt-treated type 2 diabetic KK-Ay mice, a model of human hypertensive DKD. KK-Ay mice were treated with a normal salt diet (NS: 0.3% NaCl, n = 5), high salt diet (HS: 4% NaCl, n = 8), HS + esaxerenone (1 mg/kg/day, p.o., n = 8), or HS + spironolactone, a steroidal non-selective MR antagonist (20 mg/kg/day, p.o., n = 7) for 8 weeks. Renal tissue oxidative stress was evaluated by dihydroethidium florescence intensity. HS-treated diabetic KK-Ay mice showed higher blood pressure and severe albuminuria, glomerular injury, tubulointerstitial fibrosis, renal inflammation, and oxidative stress than NS-treated diabetic KK-Ay mice. Treatment with esaxerenone or spironolactone decreased blood pressure to a similar extent in HS-treated KK-Ay mice. Conversely, esaxerenone elicited a greater attenuation of albuminuria, glomerular injury, tubulointerstitial fibrosis, and renal inflammation than spironolactone, which were associated with reduction in renal oxidative stress. These data indicate for the first time that a nonsteroidal MR antagonist elicits renoprotective effects in DKD mice.