A role for tubular Na⁺/H⁺exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin

Abstract

Inhibitors of the proximal tubular sodium glucose cotransporter SGLT2 are natriuretic and they lower blood pressure. There are reports that the activities of SGLT2 and the Na+-H+-exchanger, NHE3, are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of the SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in non-diabetic mice with tubule-specific NHE3 knock-down (NHE3-ko) and wild-type littermates (WT). A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate, and raised urine pH in WT, but not in NHE3-ko. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression, and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while co-generated and excreted ammonium balances urine losses of this "potential bicarbonate". The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors

“…Studies in mice have shown a functional relationship between SGLT2 and NHE3 (Onishi et al, 2019). In non-diabetic mice, SGLT2 inhibition with empagliflozin inhibited NHE3 activity and decreased urinary pH and bicarbonate excretion (Figure 1) (Onishi et al, 2020). Notably, chronic empagliflozin treatment in Akita mice increased a-ketoglutarate, which may drive distal sodium chloride reabsorption to compensate for the decreased proximal sodium reabsorption.…”

SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits

“…Moreover, NaCl delivery to the distal nephron reduces the glomerular filtration rate (GFR) by increasing hydrostatic pressure in Bowman’s space [ 6 ]. Natriuresis may further be promoted through the suppression of sodium–hydrogen exchanger (NHE3) activity, usually upregulated in diabetes [ 8 ].…”

Luseogliflozin, a SGLT2 Inhibitor, Does Not Affect Glucose Uptake Kinetics in Renal Proximal Tubules of Live Mice

“…Although we previously reported that inhibition of glucose uptake by SGLT2 siRNA or removal of glucose from medium is sufficient to induce cell phenotypic changes, such as suppression of cell senescence [ 14 ] or an increase in angiogenic factor secretion [ 7 ], the intracellular glucose level must be taken as the sum of glucose taken up from extracellular spaces and that generated intracellularly. SGLT2 inhibitors reportedly increase expression of genes involved in gluconeogenesis [ 15 , 16 ]. An increase in intracellular glucose production via de novo pathways may attenuate the concentration gradient of glucose between the cytosol and interstitium, thereby counteracting glucose influx through GLUT2.…”