Semaglutide reduces murine blood pressure through the vascular smooth muscle GLP-1 receptor
Kyle D. Medak, Jacqueline A. Koehler, Laurie L. Baggio, Maria J. Gonzalez-Rellan, Chi Kin Wong, Xiemin Cao, Vivikta Rao, Sean Kao, Yu Cui, Jiayi Fu, Easton Liaw, M. Golam Kabir, Jie Zhang, Jin Wei, Daniel J. Drucker
Kyle D. Medak, Jacqueline A. Koehler, Laurie L. Baggio, Maria J. Gonzalez-Rellan, Chi Kin Wong, Xiemin Cao, Vivikta Rao, Sean Kao, Yu Cui, Jiayi Fu, Easton Liaw, M. Golam Kabir, Jie Zhang, Jin Wei, Daniel J. Drucker
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Research Article Cardiology Endocrinology Metabolism

Semaglutide reduces murine blood pressure through the vascular smooth muscle GLP-1 receptor

Abstract

GLP-1 receptor (GLP-1R) agonists decrease blood glucose and body weight and reduce rates of cardiovascular and renal disease. Although GLP-1R activation lowers blood pressure (BP), the underlying mechanisms remain incompletely understood and have been attributed to weight loss and endothelial cell GLP-1R signaling. Here, we show that GLP-1Rs in vascular smooth muscle cells (VSMCs) are essential for semaglutide-mediated BP reduction in mice. In contrast, GLP-1Rs in Tie2+ endothelial or immune cells are not required for semaglutide to lower BP. The VSMC GLP-1R is dispensable for the effects of semaglutide on food intake, body weight, and blood glucose but is required for its actions to increase glomerular filtration rate and promote natriuresis. Systemic semaglutide administration resulted in proteomic changes in the renal artery and kidney in pathways related to platelet aggregation, fibrin clot formation, lipid metabolism, and proapoptotic signaling that are abolished in mice lacking VSMC GLP-1R expression. Moreover, semaglutide directly induced vasorelaxation in preconstricted mesenteric arteries ex vivo. Together, these findings identify VSMCs as a key cellular target linking GLP-1R activation to BP regulation, renal electrolyte excretion, and proteomic changes in renal artery and kidney.

Authors

Kyle D. Medak, Jacqueline A. Koehler, Laurie L. Baggio, Maria J. Gonzalez-Rellan, Chi Kin Wong, Xiemin Cao, Vivikta Rao, Sean Kao, Yu Cui, Jiayi Fu, Easton Liaw, M. Golam Kabir, Jie Zhang, Jin Wei, Daniel J. Drucker

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Figure 1

Renal GLP1R/Glp1r is expressed in human and murine vascular smooth muscle cells (VSMCs), and Glp1rVSM–/– mice have reduced Glp1r transcripts in renal tissues.

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Renal GLP1R/Glp1r is expressed in human and murine vascular smooth muscl...
(A–C) Annotation maps of the human kidney single-cell transcriptome (18), showing expression of GLP1R, and vascular smooth muscle marker α1A adrenergic receptor (ADRA1A). (D–F) An annotation map of the mouse kidney single-cell transcriptome (17), showing expression of Glp1r and VSMC marker myosin heavy chain 11 (Myh11). (G–L) Quantification of Glp1r expression relative to Rpl32 within the (G) kidney, (H) renal artery, (I) lung, (J) aortic arch, (K) abdominal aorta, and (L) carotid artery in control (Glp1rVSM+/+) and Glp1rVSM–/– male mice (n = 5–14). (M) Double immunofluorescence staining of α-smooth muscle actin (left panel), GLP-1R (middle panel) and both GLP-1R and α-smooth muscle actin (right panel) in Glp1rVSM+/+ and Glp1rVSM–/– kidney. (N) Average food intake per mouse within each cage of group housed mice over 24 hours with or without acute treatment with semaglutide in Glp1rVSM+/+ and Glp1rVSM–/– mice (n = 4–6). (O–Q) Body weight and oral glucose tolerance with calculated area under the curve in Glp1rVSM+/+ and Glp1rVSM–/– mice following acute semaglutide (10 μg/kg) treatment 120 minutes before oral glucose challenge (time 0) (n = 18–23). Data are presented as mean ± SD. ***P ≤ 0.001 and ****P ≤ 0.0001 by unpaired t test (G–L and O), or 2-way ANOVA followed by Tukey post hoc tests (N and Q). Sema, semaglutide; Veh, vehicle. Original magnification, ×31.5.