Empagliflozin inhibits proximal tubule NHE3 activity, preserves GFR and restores euvolemia in nondiabetic rats with induced heart failure

Abstract

Sodium-glucose cotransporter 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) NHE3 activity and improves renal salt and water handling in nondiabetic rats with HF. Male 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 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. Collectively, 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.

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies

“…In addition to pharmacologic inhibitors of the renin-angiotensin-aldosterone system, 9 the recent introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors shows promising renoprotective effects. 10,11 An understanding of the mechanisms of kidney function decline and the development of new therapeutic options is thus of high clinical and public health relevance. 7,12 Genes underneath genome-wide association study (GWAS) loci for diseases and biomarkers help identify new therapies.…”

Assessment of Proximal Tubular Function by Tubular Maximum Phosphate Reabsorption Capacity in Heart Failure

“…We also realize that this study does not provide definitive proof of the relationship of TmP/GFR with actual proximal tubular damage or overall reduced sodium reabsorption of the proximal tubule, as previous experimental studies in rats have detected upregulation of the NHE3 transporter in response to heart failure. (49)(50)(51) Necessity for collecting urinary samples is a disadvantage. Also, the formula is quite complex, but this can easily be solved by implementation in electronic patient systems.…”

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 TAC-induced 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 ].…”