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

被引：10

作者：

Jiang, Xiaoliang ^{[1
]}

Liu, Yunpeng ^{[1
]}

Zhang, Xin-Yang ^{[2
]}

Liu, Xue ^{[1
]}

Liu, Xing ^{[1
]}

Wu, Xianxian ^{[1
]}

Jose, Pedro A. ^{[3
,4
]}

Duan, Shun ^{[2
]}

Xu, Fu-Jian ^{[2
]}

Yang, Zhiwei ^{[1
]}

机构：

[1] CAMS&PUMC, NHC Key Lab Human Dis Comparat Med, Inst Lab Anim Sci, Natl Human Dis Anim Model Resource Ctr,Beijing En, Beijing, Peoples R China

[2] Beijing Univ Chem Technol, Key Lab Biomed Mat Nat Macromol, Minist Educ, Beijing Lab Biomed Mat,Beijing Adv Innovat Ctr So, 15 BeiSanhuan E Rd, Beijing 100029, Peoples R China

[3] George Washington Univ, Sch Med & Hlth Sci, Dept Physiol & Pharmacol, Washington, DC 20052 USA

[4] George Washington Univ, Sch Med & Hlth Sci, Dept Med, Div Kidney Dis & Hypertens, Washington, DC 20052 USA

来源：

HYPERTENSION | 2022年 / 79卷 / 08期

基金：

美国国家卫生研究院;

关键词：

blood pressure; cholecystokinin; gastrins; intestines; sodium; NHE3; ACTIVITY; RENAL-FUNCTION; SODIUM-ABSORPTION; URINARY SODIUM; PROTEIN; NATRIURESIS; ACTIVATION; EXPRESSION; EXCRETION; MORTALITY;

D O I：

10.1161/HYPERTENSIONAHA.121.18791

中图分类号：

R6 [外科学];

学科分类号：

1002 ; 100210 ;

摘要：

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 Cckbr-knockout mice (Cckbr(fl/fl) villin-Cre) and Dahl salt-sensitive rats were studied on the effect of high salt intake (8% NaCl, 6-7 weeks) on intestinal Na+/H+ 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 Cckbr(fl/fl) villin-Cre mice and Dahl salt-sensitive rats than their respective controls, Cckbr(fl/fl) villin mice and SS13(BN) rats. We constructed gastrin-SiO2 microspheres to enable gastrin to stimulate specifically and selectively intestinal CCKBR without its absorption into the circulation. Results: Gastrin-SiO2 microspheres treatment prevented the high salt-induced hypertension and increase in urine Na concentration by inhibiting intestinal Na+/H+ exchanger 3 trafficking and activity, increasing stool sodium without inducing diarrhea. Gastrin-mediated inhibition of intestinal Na+/H+ 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-SiO2 microspheres is a promising and safe strategy to treat salt-sensitive hypertension without side effects.

引用

页码：1668 / 1679

页数：12