Angiotensin II up-regulates sodium-glucose co-transporter 2 expression and SGLT2 inhibitor attenuates Ang II-induced hypertensive renal injury in mice.

Abstract

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.

• Authors: Kana N Miyata, Chao-Sheng Lo, Shuiling Zhao, Min-Chun Liao, Yuchao Pang, Shiao-Ying Chang, Junzheng Peng, Matthias Kretzler, Janos G Filep, Julie R Ingelfinger, Shao-Ling Zhang, John S D Chan
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 135 Issue 7 Pg. 943-961 (04 16 2021) ISSN: 1470-8736 [Electronic] England
• PMID: 33822013 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Angiotensin II

Topics

• 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, metabolism)
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology)