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

Methods and Results: 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 (creatinine, troponin T, and B-type natriuretic peptide). Single-nuclei RNA sequencing (snRNA-seq) and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to investigate molecular mechanisms. 5/6 nephrectomy increased serum creatinine, troponin T, LVM, ejection fraction, and cardiomyocyte diameter. Empagliflozin significantly reduced LVM and cardiomyocyte hypertrophy, comparable to Telmisartan. SnRNA-seq revealed no changes in major cardiac cell populations but identified regulation of genes critical for cardiomyocyte development, including Fhl2, Tbx20, and Angpt1. The 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.