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SGLT2 inhibition effect on salt-induced hypertension, RAAS, and Na + transport in Dahl SS rats.
- Source :
-
American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2022 Jun 01; Vol. 322 (6), pp. F692-F707. Date of Electronic Publication: 2022 Apr 25. - Publication Year :
- 2022
-
Abstract
- Na <superscript>+</superscript> -glucose cotransporter-2 (SGLT2) inhibitors are the new mainstay of treatment for diabetes mellitus and cardiovascular diseases. 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 Na <superscript>+</superscript> channels/transporters along the nephron in Dahl salt-sensitive rats, a model of salt-induced hypertension. Administration of dapagliflozin (Dapa) at 2 mg/kg/day via drinking water for 3 wk 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 <superscript>+</superscript> - and Cl <superscript>-</superscript> -to-creatinine ratios increased in Dapa-treated compared with vehicle-treated rats. To define the contribution of the RAAS, we measured various hormones. Despite apparent effects on Na <superscript>+</superscript> - and Cl <superscript>-</superscript> -to-creatinine ratios, Dapa treatment did not affect RAAS metabolites. Subsequently, we assessed the effects of Dapa on renal Na <superscript>+</superscript> channels and transporters using RT-PCR, Western blot analysis, and patch clamp. Neither mRNA nor protein expression levels of renal transporters (SGLT2, Na <superscript>+</superscript> /H <superscript>+</superscript> exchanger isoform 3, Na <superscript>+</superscript> -K <superscript>+</superscript> -2Cl <superscript>-</superscript> cotransporter 2, Na <superscript>+</superscript> -Cl <superscript>-</superscript> cotransporter, and α-, β-, and γ-epithelial Na <superscript>+</superscript> channel subunits) changed significantly between groups. Furthermore, electrophysiological experiments did not reveal any difference in Dapa treatment on the conductance and activity of epithelial Na <superscript>+</superscript> channels. Our data suggest that SGLT2 inhibition in a nondiabetic model of salt-sensitive hypertension blunts the development of salt-induced hypertension by causing glucosuria and natriuresis without changes in the RAAS or the expression or activity of the main Na <superscript>+</superscript> channels and transporters. NEW & NOTEWORTHY The present study indicates that Na <superscript>+</superscript> -glucose cotransporter-2 (SGLT2) inhibition in a nondiabetic model of salt-sensitive hypertension blunts the development and magnitude of salt-induced hypertension. Chronic inhibition of SGLT2 increases glucose and Na <superscript>+</superscript> excretion without secondary effects on the expression and function of other Na <superscript>+</superscript> transporters and channels along the nephron and hormone levels in the renin-angiotensin-aldosterone system. These data provide novel insights into the effects of SGLT2 inhibitors and their potential use in hypertension.
- Subjects :
- Animals
Blood Pressure drug effects
Creatinine metabolism
Glucose pharmacology
Rats
Rats, Inbred Dahl
Sodium Chloride, Dietary metabolism
Hypertension chemically induced
Hypertension metabolism
Nephrons drug effects
Nephrons metabolism
Renin-Angiotensin System drug effects
Sodium-Glucose Transporter 2 metabolism
Sodium-Glucose Transporter 2 Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1466
- Volume :
- 322
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Renal physiology
- Publication Type :
- Academic Journal
- Accession number :
- 35466690
- Full Text :
- https://doi.org/10.1152/ajprenal.00053.2022