Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in hypertensive patients. However, the underlying molecular mechanisms remain largely unknown. Proximal tubule (PT) NHE3-mediated sodium reabsorption is inhibited by SGLT2i in normotensive rodents, yet no BP-lowering 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. Administration of EMPA for 14 days reduced BP in 12-week-old SHRs but not in age-matched Wistar rats. PT NHE3 was inhibited by EMPA treatment in both Wistar and SHRs. EMPA increased NCC expression and phosphorylation levels in Wistar but not SHRs. SHRs exhibited higher cortical and medullary NKCC2 and β-ENaC subunit mRNA and higher medullary α-ENaC expression levels than Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP was reduced in response to EMPA and HCTZ combined but not by EMPA or HCTZ alone. Altogether, these data suggest that upregulation of NCC counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, thereby maintaining their baseline BP. Moreover, reducing NHE3 activity without further upregulation of the main apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension. FAPESP 2016/22140-7 and 2021/14534-3. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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