Cardiac and Renal Benefits of Empagliflozin in Heart Failure: Exploring Direct and Indirect Effects

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i), originally developed for type 2 diabetes (T2D), provide cardiovascular and renal benefits in heart failure (HF), regardless of T2D status. This study examined empagliflozin's (EMPA) effects on renal neurohormonal activation, cardiac remodeling, and capillary rarefaction in HF rats, alongside its direct effects on isolated rat cardiomyocytes, human coronary artery endothelial cells (HCAEC), and THP-1-derived macrophages. Methods: Male rats with myocardial infarction-induced heart failure (HF) and sham controls received empagliflozin (300 mg/kg chow) or no treatment for four weeks. Histological analyses assessed cardiac hypertrophy, fibrosis, inflammation (CD68), capillary density (CD31), and sympathetic activation (tyrosine hydroxylase). Renal cortical Ang II and urinary norepinephrine levels were determined by ELISA. Rat cardiomyocytes were treated with endothelin-1 with or without EMPA (1 µM), HCAEC were exposed to chemical hypoxia (CoCl 2 ) with or without EMPA, and THP-1 cells were differentiated into M1 or M2 macrophage phenotypes in the presence or absence of EMPA. Results: Compared to untreated HF rats, EMPA-treated HF rats displayed lower cardiomyocyte hypertrophy, interstitial fibrosis, macrophage infiltration, urinary norepinephrine concentration, and cardiac and renal tyrosine hydroxylase expression, along with increased cardiac and renal capillary density. Renal cortical Ang II concentration and macrophage counts were unchanged. However, EMPA downregulated kidney M1 macrophage markers (TNFα, iNOS, CCR2) and upregulated M2 markers (CD206, Arg-1, CD163). Cardiomyocyte area increased with endothelin exposure but was smaller with EMPA co-treatment. CoCl 2 reduced EdU-positive HCAEC, while EMPA prevented this reduction and increased EdU-positive cells on its own. EMPA alone did not affect THP-1 polarization or enhance IL-4-induced M2 or IFNγ/LPS-induced M1 polarization. Conclusion: Empagliflozin enhances angiogenesis and reduces cardiac remodeling in heart failure, potentially mediated in part by its direct effects on cardiomyocytes and endothelial cells. However, EMPA does not directly influence macrophage polarization or renal Ang II levels. São Paulo Research Foundation (FAPESP; #2020/02668-2; #2021/14534-3; #2024/09267-4) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.