Renal upregulation of NCC counteracts empagliflozin-mediated NHE3 inhibition in normotensive but not in hypertensive male rat

Author(s)

Castro, Paulo C. ; Santos-Rios, Thiago M. ; Martins, Flavia L. ; Crajoinas, Renato O. ; Caetano, Marcos V. ; Lessa, Lucilia M. A. ; Luchi, Weverton M. ; McCormick, James A. ; Girardi, Adriana C. C.

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY; v. 326, n. 6, p. 17-pg., 2024-06-01.

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in patients with hypertension, yet the precise molecular mechanisms remain elusive. SGLT2i inhibits proximal tubule (PT) NHE3-mediated sodium reabsorption in normotensive rodents, yet no hypotensive effect is observed under this scenario. This study examined the effect of empagliflozin (EMPA) on renal tubular sodium transport in normotensive and spontaneously hypertensive rats (SHRs). It also tested the hypothesis that EMPA-mediated PT NHE3 inhibition in normotensive rats is associated with upregulation of distal nephron apical sodium transporters. EMPA administration for 14 days reduced BP in 12-wk-old SHRs but not in age-matched Wistar rats. PT NHE3 activity was inhibited by EMPA treatment in both Wistar and SHRs. In Wistar rats, EMPA increased NCC activity, mRNA expression, protein abundance, and phosphorylation levels, but not in SHRs. SHRs showed higher NKCC2 activity and an abundance of cleaved ENaC alpha and gamma subunits compared with Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), and EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP reduction was observed only with combined EMPA and HCTZ treatment, not with either drug alone. These findings suggest that NCC upregulation counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, maintaining their baseline BP. Moreover, the reduction of NHE3 activity without further upregulation of major apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension. (AU)

• FAPESP's process: 21/14534-3 - Pleiotropic effects of antidiabetic agents and their pharmacological targets: renoprotective mechanisms beyond glycemic control
• Grantee: Adriana Castello Costa Girardi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/22140-7 - Molecular bases of renal tubular function and dysfunction
• Grantee: Adriana Castello Costa Girardi
• Support Opportunities: Research Projects - Thematic Grants