Angiotensin II up-regulates sodium-glucose co-transporter 2 expression and SGLT2 inhibitor attenuates Ang II-induced hypertensive renal injury in mice.
Adult
Angiotensin II
/ pharmacology
Animals
Cell Line
Female
Humans
Hypertension
/ chemically induced
Kidney Diseases
/ physiopathology
Male
Mice
Mice, Transgenic
Middle Aged
Renin-Angiotensin System
/ drug effects
Sodium-Glucose Transporter 2
/ genetics
Sodium-Glucose Transporter 2 Inhibitors
/ pharmacology
Angiotensin II
Hypertension
Intrarenal RAS
SGLT2
Transgenic mice
tubulointerstitial fibrosis
Journal
Clinical science (London, England : 1979)
ISSN: 1470-8736
Titre abrégé: Clin Sci (Lond)
Pays: England
ID NLM: 7905731
Informations de publication
Date de publication:
16 04 2021
16 04 2021
Historique:
received:
28
01
2021
revised:
01
04
2021
accepted:
06
04
2021
pubmed:
7
4
2021
medline:
2
10
2021
entrez:
6
4
2021
Statut:
ppublish
Résumé
Clinical trials indicate that sodium/glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, n=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) mRNA levels (P<0.001). In vitro, angiotensin II (Ang II) dose-dependently stimulated SGLT2 expression in HK-2, human immortalized renal proximal tubular cells (RPTCs); losartan and antioxidants inhibited it. Sglt2 expression was increased in transgenic (Tg) mice specifically overexpressing Agt in their RPTCs, as well as in WT mice with a single subcutaneous injection of Ang II (1.44 mg/kg). Moreover, Ang II (1000 ng/kg/min) infusion via osmotic mini-pump in WT mice for 4 weeks increased systolic blood pressure (SBP), glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria; canaglifozin (Cana, 15 mg/kg/day) reversed these changes, with the exception of SBP. Fractional glucose excretion (FeGlu) was higher in Ang II+Cana than WT+Cana, whereas Sglt2 expression was similar. Our data demonstrate a link between intrarenal RAS and SGLT2 expression and that SGLT2i ameliorates Ang II-induced renal injury independent of SBP.
Identifiants
pubmed: 33822013
pii: 228217
doi: 10.1042/CS20210094
pmc: PMC8131957
mid: NIHMS1696468
doi:
Substances chimiques
Sodium-Glucose Transporter 2
0
Sodium-Glucose Transporter 2 Inhibitors
0
Angiotensin II
11128-99-7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
943-961Subventions
Organisme : NIDDK NIH HHS
ID : U54 DK083912
Pays : United States
Organisme : CIHR
ID : MOP-84363
Pays : Canada
Organisme : CIHR
ID : MOP-142378
Pays : Canada
Organisme : CIHR
ID : MOP-86450
Pays : Canada
Organisme : CIHR
ID : MOP-97742
Pays : Canada
Informations de copyright
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
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