SGLT2 inhibition effect on salt-induced hypertension, RAAS, and Na⁺ transport in Dahl SS rats

Abstract

SGLT2 inhibitors are the new mainstay of diabetes mellitus and cardiovascular diseases treatment. Despite the remarkable benefits, the molecular mechanisms mediating the effects of SGLT2 inhibitors on water and electrolyte balance are incompletely understood. The goal of this study was to determine whether SGLT2 inhibition alters blood pressure and kidney function via affecting the Renin-Angiotensin-Aldosterone System (RAAS) and sodium channels/transporters along the nephron in Dahl Salt-Sensitive (SS) rats, a model of salt-induced hypertension. Administration of dapagliflozin (Dapa) at 2 mg/kg/day via drinking water for 3 weeks blunted the development of salt-induced hypertension as evidenced by lower blood pressure and a left shift of the pressure natriuresis curve. Urinary flow rate, glucose excretion, and Na+ and Cl-/creatinine ratios increased in Dapa-treated compared to vehicle-treated rats. To define the contribution of RAAS, we measured various hormones. Despite apparent effects on Na+ and Cl-/creatinine ratios, Dapa treatment did not affect RAAS metabolites. Subsequently, we assessed the effects of Dapa on renal Na+ channels and transporters using RT-PCR, Western blotting, and patch-clamp. Neither mRNA nor protein expression levels of tested renal transporters (SGLT2, NHE3, NKCC2, NCC, and α-, β-, γ- ENaC subunits) changed significantly between groups. Furthermore, electrophysiological studies did not reveal any difference in Dapa treatment on the conductance and activity of ENaC. Our data suggest that SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension blunts the development of salt-induced hypertension by causing glucosuria and natriuresis without changes in RAAS and expression or activity of studied Na+ channels and transporters.

Empagliflozin increases kidney weight due to increased cell size in the proximal tubule S3 segment and the collecting duct

“…In correlation with these findings, the mRNA expression of ENaC was increased in enlarged collecting ducts of EMPA-treated animals ( Figure 4A ) supporting the proposed concept of increased reabsorption workload in this segment. The rather small effect on mRNA expression of the ENaC subunits was not found on protein level ( Supplementary figure S5 ) and the literature is very contradictory regarding the regulation of renal sodium transporters by SGLT2 inhibitors ranging from no effect ( Chen L. et al, 2016 ; Kravtsova et al, 2022 ), reduced expression ( Chung et al, 2019 ) or increased expression ( Ma et al, 2019 ). It has to be mentioned that only this study used healthy wildtype animals, while most expression analysis data derive from rodent disease models for diabetes or salt-induced hypertension, treatments known to affect renal Na + handling itself.…”

Metabolic Communication by SGLT2 Inhibition

“…Urine and serum were obtained from dapagliflozin- and vehicle-treated hypertensive animals as described in a previous study by Kravtsova et al 44 and analyzed as described previously.…”

“…Urine and serum were obtained from dapagliflozin-and vehicletreated hypertensive animals as described in a previous study by Kravtsova et al 44 and analyzed as described previously. Each fecal sample was transferred to a sealed bag containing a CO 2 gas pack (BD GasPak EZ pouch system) immediately, as described, 45 and was processed within 4 hours after defecation.…”

Pathophysiology and genetics of salt-sensitive hypertension

“…The potential use of Na + -glucose cotransporter-2 inhibitors (SGLT2i) in salt-sensitive HTN and associated renal diseases has also generated much interest. A recent study found that dapagliflozin 2 mg/kg/day ameliorated HTN, improved pressure natriuresis and increased urinary flow rate, glucosuria, and Na + - and Cl − -to-creatinine ratios in Dahl salt-sensitive rats ( Kravtsova et al, 2022 ). Interestingly, in that study, no changes in the expression of RAAS metabolites or in Na + channels SGLT2, NKCC, NHE3, NCC and ENaC was observed.…”