Empagliflozin inhibits proximal tubule NHE3 activity, preserves GFR and restores euvolemia in non-diabetic heart failure rats

BackgroundSodium-glucose cotransporter type 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. We tested the hypothesis that the SGLT2 inhibitor empagliflozin inhibits proximal tubule (PT) Na+/H+ exchanger isoform 3 (NHE3) activity and improves renal salt and water handling in nondiabetic rats with HF. Methods and ResultsMale Wistar rats were subjected to myocardial infarction or sham operation. After four weeks, rats that developed HF and sham rats were treated with empagliflozin (EMPA) or untreated for an additional four weeks. EMPA-treated HF rats displayed lower levels of serum brain natriuretic peptide (BNP) and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment normalized the glomerular filtration rate and proteinuria in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 function and protein and mRNA abundance were upregulated in the PT of HF rats. ConclusionCollectively, our data show that the prevention of HF progression by empagliflozin is associated with inhibition of PT NHE3 activity and restoration of euvolemia. Moreover, we propose that the dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF. SIGNIFICANCE STATEMENTSGLT2 inhibitors represent a class of drugs that were originally developed for improving glycemic control. Cardiovascular outcome trials that were designed to evaluate cardiovascular safety yielded unexpected and unprecedented evidence of the cardiorenal benefits of SGLT2 inhibitor. Many hypotheses have been proposed to explain the mechanisms underlying these effects. Our study demonstrates that SGLT2 inhibition restores extracellular volume homeostasis in nondiabetic heart failure (HF) rats by preserving GFR and inhibiting proximal tubule NHE3-mediated sodium reabsorption. The attenuation of kidney dysfunction may constitute an essential mechanism by which SGLT2 inhibitors attenuate HF development and progression either in the presence or absence of diabetes.