| Authors |
Kravtsova O, Bohovyk R, Levchenko V, Palygin O, Klemens CA, Rieg T, Staruschenko
A
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| Submitted By |
Submitted Externally on 6/13/2022 |
| Status |
Published |
| Journal |
American journal of physiology. Renal physiology |
| Year |
2022 |
| Date Published |
6/1/2022 |
| Volume : Pages |
322 : F692 - F707 |
| PubMed Reference |
35466690 |
| Abstract |
Na+-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+
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+- and
Cl--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+- and Cl--to-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 blot analysis, and
patch clamp. Neither mRNA nor protein expression levels of renal transporters
(SGLT2, Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter 2, Na+-Cl-
cotransporter, and a-, ß-, and ?-epithelial Na+ 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+ 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+ channels and transporters.NEW &
NOTEWORTHY The present study indicates that Na+-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+ excretion without secondary effects on the
expression and function of other Na+ 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.
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