Cardiorenal protective effect of SGLT2i empagliflozin in a novel mouse model of uremic cardiomyopathy via regulating the Nrf2-mediated oxidative stress

Uremic cardiomyopathy (UCM), characterized by left ventricular hypertrophy, myocardial fibrosis, and predominant diastolic dysfunction, is a major contributor to cardiovascular mortality in end-stage renal disease (ESRD). Progress in mechanistic and therapeutic research has been hindered by the lack of preclinical models that faithfully reproduce the integrated cardiac and renal phenotype observed in patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiorenal protective effects in chronic kidney disease beyond glycemic control; however, their therapeutic relevance to UCM remains largely unexplored. This study aimed to establish a clinically relevant, time-efficient UCM mouse model using a “multifactorial hit” strategy and to evaluate the protective potential of empagliflozin (EMPA) in this context.

Uremic cardiomyopathy (UCM), characterized by left ventricular hypertrophy, myocardial fibrosis, and predominant diastolic dysfunction, is a major contributor to cardiovascular mortality in end-stage renal disease (ESRD). Progress in mechanistic and therapeutic research has been hindered by the lack of preclinical models that faithfully reproduce the integrated cardiac and renal phenotype observed in patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiorenal protective effects in chronic kidney disease beyond glycemic control; however, their therapeutic relevance to UCM remains largely unexplored. This study aimed to establish a clinically relevant, time-efficient UCM mouse model using a “multifactorial hit” strategy and to evaluate the protective potential of empagliflozin (EMPA) in this context.

Both 5/6 Nx and UCM mice developed comparable renal dysfunction, as indicated by elevated serum creatinine and urea. However, only the multifactorial UCM model exhibited marked hypertension, left ventricular dilation and hypertrophy, impaired systolic and diastolic function, and histological evidence of myocardial hypertrophy and interstitial fibrosis. These findings demonstrate that additional hemodynamic and metabolic stresses are required to elicit the cardiac phenotype characteristic of clinical UCM, which was not observed in the conventional 5/6 Nx model.

EMPA treatment significantly improved renal function, reduced systemic blood pressure, and attenuated glomerulosclerosis and tubulointerstitial fibrosis in UCM mice. In the heart, EMPA ameliorated ventricular hypertrophy, improved diastolic relaxation, and reduced myocardial fibrosis. ROS accumulation in cardiac and renal tissues was markedly suppressed, accompanied by downregulation of pro-inflammatory genes (Il6, Il1b, Tnf). Mechanistically, EMPA enhanced activation of the Nrf2/ARE pathway, with increased expression of Nrf2, NQO1, and HO-1, suggesting mitigation of oxidative stress as a key mechanism underlying its protective effects.

This study introduces a novel, clinically relevant UCM mouse model that more accurately recapitulates the integrated cardiorenal pathology of ESRD than conventional models. Empagliflozin confers significant cardiorenal protection in this model, likely through antioxidant and anti-inflammatory mechanisms mediated by Nrf2/ARE activation. These findings provide a valuable platform for mechanistic studies and support further exploration of SGLT2 inhibition as a therapeutic strategy for UCM.