Eplerenone improves kidney function and cardiac performance in obese male mice

TY - JOUR

T1 - Eplerenone improves kidney function and cardiac performance in obese male mice

AU - Banah, Ayman K.

AU - Qi, Bingxue

AU - Koh, Ryan

AU - Lawlor, Alexander

AU - Wang, Tianzhen

AU - Musale, Vishal

AU - Mains, Joanne

AU - Murdoch, Colin E.

AU - Kang, Li

N1 - Publisher Copyright: © 2025 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

PY - 2026/1

Y1 - 2026/1

N2 - Aims: Renin-angiotensin-aldosterone system (RAAS) activation mediates obesity-associated cardiorenal dysfunction. Due to an incomplete understanding of the molecular mechanisms, the clinical use of RAAS antagonism in obesity-associated cardiometabolic complications remains uncertain. The present study investigated the effects and associated molecular mechanisms of eplerenone, a selective mineralocorticoid receptor antagonist, in the heart and kidney of obesity. Methods: Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks before receiving either vehicle or eplerenone treatments for 30 days while maintained on HFD. Cardiac function was measured by pressure–volume (PV) loop analyses. Renal function was assessed by renal morphology and serum creatinine concentrations. Chow-fed mice were used as lean controls. Results: HFD feeding impaired cardiac and renal function in mice, evidenced by elevated blood pressures, stroke work, Tau, glomerular hypertrophy and tubular injury. Eplerenone treatment caused weight loss, which was attributed to a loss in fat mass. Moreover, eplerenone treatment ameliorated both HFD-induced cardiac and renal dysfunction, including a decrease in stroke volume, cardiac output and stroke work; an increase in ejection fraction; and a decrease in glomerular hypertrophy, tubular injury, renal fibrosis and serum creatinine concentrations. Mechanistically, eplerenone decreased CD44 but increased RHAMM and TGF-β expression in the heart. In contrast, eplerenone caused a decrease in the hyaluronan-CD44/RHAMM pathway, TGF-β, IL-6 and phosphorylation of Akt and JNK in the kidney. Conclusion: Eplerenone treatment improved kidney function and cardiac performance in obese male mice. The potential link between the mineralocorticoid receptor and the hyaluronan-CD44/RHAMM pathway is novel and has not been previously reported.

AB - Aims: Renin-angiotensin-aldosterone system (RAAS) activation mediates obesity-associated cardiorenal dysfunction. Due to an incomplete understanding of the molecular mechanisms, the clinical use of RAAS antagonism in obesity-associated cardiometabolic complications remains uncertain. The present study investigated the effects and associated molecular mechanisms of eplerenone, a selective mineralocorticoid receptor antagonist, in the heart and kidney of obesity. Methods: Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks before receiving either vehicle or eplerenone treatments for 30 days while maintained on HFD. Cardiac function was measured by pressure–volume (PV) loop analyses. Renal function was assessed by renal morphology and serum creatinine concentrations. Chow-fed mice were used as lean controls. Results: HFD feeding impaired cardiac and renal function in mice, evidenced by elevated blood pressures, stroke work, Tau, glomerular hypertrophy and tubular injury. Eplerenone treatment caused weight loss, which was attributed to a loss in fat mass. Moreover, eplerenone treatment ameliorated both HFD-induced cardiac and renal dysfunction, including a decrease in stroke volume, cardiac output and stroke work; an increase in ejection fraction; and a decrease in glomerular hypertrophy, tubular injury, renal fibrosis and serum creatinine concentrations. Mechanistically, eplerenone decreased CD44 but increased RHAMM and TGF-β expression in the heart. In contrast, eplerenone caused a decrease in the hyaluronan-CD44/RHAMM pathway, TGF-β, IL-6 and phosphorylation of Akt and JNK in the kidney. Conclusion: Eplerenone treatment improved kidney function and cardiac performance in obese male mice. The potential link between the mineralocorticoid receptor and the hyaluronan-CD44/RHAMM pathway is novel and has not been previously reported.

KW - Eplerenone

KW - fibrosis

KW - cardio-renal dysfunction

KW - obesity

KW - eplerenone

UR - https://www.scopus.com/pages/publications/105018336672

U2 - 10.1111/dme.70154

DO - 10.1111/dme.70154

M3 - Article

C2 - 41042601

SN - 0742-3071

VL - 43

JO - Diabetic Medicine

JF - Diabetic Medicine

IS - 1

M1 - e70154

ER -