Intestinal Gastrin/CCKBR (Cholecystokinin B Receptor) Ameliorates Salt-Sensitive Hypertension by Inhibiting Intestinal Na/H Exchanger 3 Activity Through a PKC (Protein Kinase C)-Mediated NHERF1 and NHERF2 Pathway

Xiaoliang Jiang, NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.).
Yunpeng Liu, NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.).
Xin-Yang Zhang, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, P.R. China (X.-Y.Z., S.D., F.-J.X.).
Xue Liu, NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.).
Xing Liu, NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.).
Xianxian Wu, NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.).
Pedro A. Jose, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC. (P.A.J.).
Shun Duan, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, P.R. China (X.-Y.Z., S.D., F.-J.X.).
Fu-Jian Xu, Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, P.R. China (X.-Y.Z., S.D., F.-J.X.).
Zhiwei Yang, NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.).

Document Type

Journal Article

Publication Date

6-8-2022

Journal

Hypertension (Dallas, Tex. : 1979)

DOI

10.1161/HYPERTENSIONAHA.121.18791

Keywords

blood pressure; cholecystokinin; gastrins; intestines; sodium

Abstract

BACKGROUND: The present study directly tested the crucial role of intestinal gastrin/CCKBR (cholecystokinin B receptor) in the treatment of salt-sensitive hypertension. METHODS: Adult intestine-specific -knockout mice ( ) and Dahl salt-sensitive rats were studied on the effect of high salt intake (8% NaCl, 6-7 weeks) on intestinal NaH exchanger 3 expression, urine sodium concentration, and blood pressure. High-salt diet increased urine sodium concentration and systolic blood pressure to a greater extent in mice and Dahl salt-sensitive rats than their respective controls, mice and SS13 rats. We constructed gastrin-SiO microspheres to enable gastrin to stimulate specifically and selectively intestinal CCKBR without its absorption into the circulation. RESULTS: Gastrin-SiO microspheres treatment prevented the high salt-induced hypertension and increase in urine Na concentration by inhibiting intestinal NaH exchanger 3 trafficking and activity, increasing stool sodium without inducing diarrhea. Gastrin-mediated inhibition of intestinal NaH exchanger 3 activity, related to a PKC (protein kinase C)-mediated activation of NHERF1 and NHERF2. CONCLUSIONS: These results support a crucial role of intestinal gastrin/CCKBR in decreasing intestinal sodium absorption and keeping the blood pressure in the normal range. The gastrointestinal administration of gastrin-SiO microspheres is a promising and safe strategy to treat salt-sensitive hypertension without side effects.

Department

Medicine

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