Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure

Abstract

BackgroundSGLT2 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. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling.MethodsMale Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity.ResultsEMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels 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 prevented GFR decline and renal atrophy 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 protein and mRNA abundance were upregulated in the PT of HF rats.ConclusionsPrevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.

Deletion of heterogeneous nuclear ribonucleoprotein F in renal tubules downregulates SGLT2 expression and attenuates hyperfiltration and kidney injury in a mouse model of diabetes

“…This difference may be related to increased Ang II in Akita Hnrnpf RT KO mice since Ang II has been shown to stimulate NHE3 expression [41]. Moreover, studies have demonstrated a discrepancy between NHE3 mRNA expression, protein expression and transporter activity, and post-transcriptional NHE3 phosphorylation is also an important factor [36,42]. Therefore, it is still unclear if changes in NHE3 activity contributes to TGF and natriuresis in Akita Hnrnpf RT KO mice.…”

“…4d) were higher in Akita mice than in Ctrl mice and were markedly lower in Akita Hnrnpf RT KO mice as compared with Akita mice. Recent studies have suggested that the reduction of Na + /H + exchanger isoform 3 (NHE3) activity is the determinant of natriuretic effect of SGLT2i [34][35][36]. Therefore, we also evaluated the Nhe3 (also known as Slc9a3) expression in Akita Hnrnpf RT KO mice.…”

Cardioprotection by SGLT2 Inhibitors—Does It All Come Down to Na+?

“…In a rat model of myocardial infarction (MI)-induced heart failure empagliflozin (start of administration 4 weeks after MI and continued for further 4 weeks) slightly improved contractile function and prevented renal insufficiency. Apart from normalization of increased SGLT2 expression these effects were primarily ascribed to inhibition of renal NHE3 [123]. Unfortunately, it remains unclear if the amelioration of cardiac dysfunction in this study of cardiorenal syndrome is due to improved renal function or due to direct cardiac effects [123].…”

“…Apart from normalization of increased SGLT2 expression these effects were primarily ascribed to inhibition of renal NHE3 [123]. Unfortunately, it remains unclear if the amelioration of cardiac dysfunction in this study of cardiorenal syndrome is due to improved renal function or due to direct cardiac effects [123]. Interestingly, in a non-diabetic mouse model of TACinduced heart failure, empagliflozin treatment prevented worsening of LVEF assessed by echocardiography in vivo as well as ex vivo by an isolated perfused working heart system (excluding a role of extrinsic factors such as hemodynamics or nephroprotection) [124].…”

The dawn of a new era of targeted therapies for heart failure with preserved ejection fraction (HFpEF)

“…Recent preclinical and clinical research has shown that SGLT2-i treatment provides cardiovascular benefits [6][7][8][9]. The early benefits of treatment with an SGLT2-i to prevent clinical deterioration in the EMPEROR-Preserved trial [1] may indicate the possibility of a natriuretic effect, as an acute increase in urinary sodium excretion was caused by the SGLT2-i empagliflozin in a nondiabetic rat model with induced heart failure [10]. Similarly, reports of beneficial action mechanisms in basic research and favorable clinical results for heart failure in ARNI therapy have increased in recent years [11][12][13].…”