Empagliflozin reduces left ventricular mass increase and improves cardiomyocyte hypertrophy after 5/6 nephrectomy

Left ventricular hypertrophy (LVH) is a common cardiac complication in patients with cardiorenal syndrome. Empagliflozin has demonstrated cardio-renal protective effects in clinical studies, potentially linked to reductions in left ventricular mass (LVM). Using a 5/6 nephrectomy rat model to induce cardiorenal syndrome, we administered two doses of Empagliflozin (3 mg/kg/day and 15 mg/kg/day) via gavage for 95 days, with Telmisartan as a positive control. Cardiac structure and function were assessed using echocardiography, histological analysis, and serum biomarkers. Single-nucleus RNA sequencing (snRNA-seq) and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to investigate molecular mechanisms. The 5/6 nephrectomy increased serum creatinine, troponin T, LVM, ejection fraction, and cardiomyocyte diameter. Empagliflozin treatment significantly decreased LVM and cardiomyocyte hypertrophy, comparable to Telmisartan. snRNA-seq revealed no changes in major cardiac cell populations but identified differential expression of cardiomyocyte development genes, including Fhl2, Tbx20, and Angpt1. qRT-PCR data for Fhl2 and Tbx20 aligned with the snRNA-seq data, showing that Empagliflozin increased Fhl2 expression and decreased Tbx20 expression. Immunofluorescence showed increased myocardial infiltration of M2 macrophages, CD4 + T cells, and CD8 + T cells in Empagliflozin-treated rats, but there was no difference between the 5/6 nephrectomized rats and normal rats. In a non-diabetic cardiorenal syndrome model, Empagliflozin effectively attenuated left ventricular hypertrophy and cardiomyocyte enlargement. These effects appear mediated by the regulation of genes involved in cardiomyocyte development and myocardial remodeling (Fhl2 and Tbx20), rather than cardiomyocyte proliferation. These findings highlight Empagliflozin's cardioprotective potential in cardiorenal syndrome and provide a foundation for further clinical exploration.