SGLT2 Inhibitor-Induced Sympathoinhibition: A Novel Mechanism for Cardiorenal Protection

Lakshini Y Herat; Aaron L Magno; Caroline Rudnicka; Jana Hricova; Revathy Carnagarin; Natalie C Ward; Angelique Arcambal; Marcio G Kiuchi; Geoff A Head; Markus P Schlaich; Vance B Matthews

doi:10.1016/j.jacbts.2019.11.007

SGLT2 Inhibitor-Induced Sympathoinhibition: A Novel Mechanism for Cardiorenal Protection

JACC Basic Transl Sci. 2020 Jan 29;5(2):169-179. doi: 10.1016/j.jacbts.2019.11.007. eCollection 2020 Feb.

Authors

Lakshini Y Herat¹, Aaron L Magno², Caroline Rudnicka², Jana Hricova¹, Revathy Carnagarin³, Natalie C Ward^{4

5

6}, Angelique Arcambal^{4

7}, Marcio G Kiuchi³, Geoff A Head⁸, Markus P Schlaich^{3

9}, Vance B Matthews¹

Affiliations

¹ Dobney Hypertension Centre, School of Biomedical Science, Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.
² Research Centre, Royal Perth Hospital, Perth, Australia.
³ Dobney Hypertension Centre, School of Medicine, Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.
⁴ School of Medicine, Royal Perth Hospital, University of Western Australia, Perth, Australia.
⁵ School of Public Health, Curtin University, Perth, Australia.
⁶ Curtin Health Innovation Research Institute, Curtin University, Perth, Australia.
⁷ Université de La Réunion, Saint-Denis, Réunion, France.
⁸ Baker Heart and Diabetes Institute, Melbourne, Australia.
⁹ Department of Cardiology and Department of Nephrology, Royal Perth Hospital, Perth, Australia.

Abstract

Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction. These findings provide evidence for significant crosstalk between activation of the sympathetic nervous system and SGLT2 regulation and possible ancillary effects on endothelial function, which may contribute to the observed cardiorenal protective effects of SGLT2 inhibition.

Keywords: 6-OHDA, 6-hydroxydopamine; DBP, diastolic blood pressure; ELISA, enzyme-linked immunosorbent assay; HFD, high-fat diet; MAP, mean arterial pressure; SBP, systolic blood pressure; SCFA, short-chain fatty acid; SGLT2; SGLT2, sodium glucose cotransporter 2; SNS, sympathetic nervous system; denervation; heart; hypertension; kidney; sympathetic nervous system.