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

Akira Onishi, Yiling Fu, Rohit Patel, Manjula Darshi, Maria Crespo-Masip, Winnie Huang, Panai Song, Brent Freeman, Young Chul Kim, Manoocher Soleimani, Kumar Sharma, Scott Culver Thomson, Volker Vallon

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (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 an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. 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 cogenerated and excreted ammonium balances urine losses of this “potential bicarbonate.” The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

Original languageEnglish (US)
Pages (from-to)F712-F728
JournalAmerican Journal of Physiology - Renal Physiology
Issue number4
StatePublished - Oct 2020


  • Azelaic acid
  • Kidney metabolism
  • Na-glucose cotransporter 2 inhibitor
  • Na/H exchanger
  • Natriuresis
  • Proximal tubule

ASJC Scopus subject areas

  • Physiology
  • Urology


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