Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker

Abstract

Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin-angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2'-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K⁺ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (-1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K⁺ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.

Keywords: Albuminuria; Angiotensin II receptor blocker; Diabetic nephropathy; Esaxerenone; Mineralocorticoid receptor blocker.

Fig. 1

Urinary albumin-to-creatinine ratio (UACR) (a), urinary albumin excretion (Ualb) (b), fasting blood glucose (c), and insulin (d) in KK-Ay mice at 8 or 9 weeks of age. The data are given as the mean ± standard error. ^##P < 0.01 vs. C57BL/6 J (comparison between two groups)

Fig. 2

Effect of combined treatment with esaxerenone and olmesartan on the urinary albumin-to-creatinine ratio (UACR). a Time course of ∆UACR (change from baseline). b AUC of ∆UACR from 0 to 8 weeks. The data are given as the mean ± standard error. **P < 0.002 vs. vehicle (Bonferroni correction)

Fig. 3

Effect of combination treatment with esaxerenone and olmesartan on systolic blood pressure (a), fasting blood glucose (b), and serum K⁺ level (c). Neither esaxerenone, olmesartan, nor combination treatment had any significant effect on systolic blood pressure, fasting blood glucose, or serum K⁺ levels. The data are given as the mean ± standard error. ^##P < 0.01 vehicle vs. control (comparison between two groups)

Fig. 4

Effects of combination treatment with esaxerenone and olmesartan on urinary podocalyxin (a), MCP-1 (b), and 8-OHdG (c) excretion from 0 to 8 weeks in KK-Ay mice. Esaxerenone, olmesartan, or both were orally administered to KK-Ay mice once a day for 8 weeks. Twenty-four-hour urine collection was performed in weeks 0, 4, and 8. Urinary concentrations of each substance were measured, and urinary excretion for 24 h was calculated. The data are given as the mean ± standard error. MCP-1 monocyte chemoattractant protein-1, 8-OHdG 8-hydroxy-2’-deoxyguanosine. ^##P < 0.01 vs. control (comparison between two groups); *P < 0.01 vs. vehicle (Bonferroni correction); ^$P < 0.01 vs. olmesartan (Bonferroni correction)