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

Overview

Journal Hypertension

Date 2022 Jun 8

PMID 35674015

Authors

Xiaoliang Jiang

Yunpeng Liu

Xin-Yang Zhang

Xue Liu

Xing Liu

Xianxian Wu

Pedro A Jose

Shun Duan

Fu-Jian Xu

Zhiwei Yang

Affiliations

Soon will be listed here.

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.

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References

Yang J, Jose P, Zeng C . Gastrointestinal-Renal Axis: Role in the Regulation of Blood Pressure. J Am Heart Assoc. 2017; 6(3). PMC: 5524043. DOI: 10.1161/JAHA.117.005536. View

Ledoussal C, Woo A, Miller M, Shull G . Loss of the NHE2 Na(+)/H(+) exchanger has no apparent effect on diarrheal state of NHE3-deficient mice. Am J Physiol Gastrointest Liver Physiol. 2001; 281(6):G1385-96. DOI: 10.1152/ajpgi.2001.281.6.G1385. View

Murtazina R, Kovbasnjuk O, Donowitz M, Li X . Na+/H+ exchanger NHE3 activity and trafficking are lipid Raft-dependent. J Biol Chem. 2006; 281(26):17845-55. DOI: 10.1074/jbc.M601740200. View

Cui J, Zhou X, Chazaro I, DeStefano A, Manolis A, Baldwin C . Association of polymorphisms in the promoter region of the PNMT gene with essential hypertension in African Americans but not in whites. Am J Hypertens. 2003; 16(10):859-63. DOI: 10.1016/s0895-7061(03)01026-4. View

Li X, Shull G, Miguel-Qin E, Chen F, Zhuo J . Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines. Physiol Rep. 2015; 3(11). PMC: 4673635. DOI: 10.14814/phy2.12605. View

Broere N, Chen M, Cinar A, Singh A, Hillesheim J, Riederer B . Defective jejunal and colonic salt absorption and alteredNa(+)/H (+) exchanger 3 (NHE3) activity in NHE regulatory factor 1 (NHERF1) adaptor protein-deficient mice. Pflugers Arch. 2008; 457(5):1079-91. PMC: 3746809. DOI: 10.1007/s00424-008-0579-1. View

Li X, Shull G, Miguel-Qin E, Zhuo J . Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension. Physiol Genomics. 2015; 47(10):479-87. PMC: 4593829. DOI: 10.1152/physiolgenomics.00056.2015. View

Cha B, Donowitz M . The epithelial brush border Na+/H+ exchanger NHE3 associates with the actin cytoskeleton by binding to ezrin directly and via PDZ domain-containing Na+/H+ exchanger regulatory factor (NHERF) proteins. Clin Exp Pharmacol Physiol. 2008; 35(8):863-71. DOI: 10.1111/j.1440-1681.2008.04931.x. View

Yang J, Singh V, Cha B, Chen T, Sarker R, Murtazina R . NHERF2 protein mobility rate is determined by a unique C-terminal domain that is also necessary for its regulation of NHE3 protein in OK cells. J Biol Chem. 2013; 288(23):16960-16974. PMC: 3675628. DOI: 10.1074/jbc.M113.470799. View

10.

Seidler U, Singh A, Cinar A, Chen M, Hillesheim J, Hogema B . The role of the NHERF family of PDZ scaffolding proteins in the regulation of salt and water transport. Ann N Y Acad Sci. 2009; 1165:249-60. DOI: 10.1111/j.1749-6632.2009.04046.x. View

11.

Wang Z, Zeng C, Villar V, Chen S, Konkalmatt P, Wang X . Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension. 2015; 67(2):325-34. PMC: 4713262. DOI: 10.1161/HYPERTENSIONAHA.115.05962. View

12.

Zhu X, Cha B, Zachos N, Sarker R, Chakraborty M, Chen T . Elevated calcium acutely regulates dynamic interactions of NHERF2 and NHE3 proteins in opossum kidney (OK) cell microvilli. J Biol Chem. 2011; 286(40):34486-96. PMC: 3186394. DOI: 10.1074/jbc.M111.230219. View

13.

Anbazhagan A, Priyamvada S, Alrefai W, Dudeja P . Pathophysiology of IBD associated diarrhea. Tissue Barriers. 2018; 6(2):e1463897. PMC: 6179131. DOI: 10.1080/21688370.2018.1463897. View

14.

Wang J, Zhao L, Zhu J, Wang D, Ren M, Wang M . Expression, Localization, and Effect of High Salt Intake on Electroneutral Na/HCO Cotransporter NBCn2 in Rat Small Intestine: Implication in Intestinal NaCl Absorption. Front Physiol. 2019; 10:1334. PMC: 6828735. DOI: 10.3389/fphys.2019.01334. View

15.

Graudal N, Jurgens G, Baslund B, Alderman M . Compared with usual sodium intake, low- and excessive-sodium diets are associated with increased mortality: a meta-analysis. Am J Hypertens. 2014; 27(9):1129-37. DOI: 10.1093/ajh/hpu028. View

16.

Girardi A, Di Sole F . Deciphering the mechanisms of the Na+/H+ exchanger-3 regulation in organ dysfunction. Am J Physiol Cell Physiol. 2012; 302(11):C1569-87. DOI: 10.1152/ajpcell.00017.2012. View

17.

Grillo A, Salvi L, Coruzzi P, Salvi P, Parati G . Sodium Intake and Hypertension. Nutrients. 2019; 11(9). PMC: 6770596. DOI: 10.3390/nu11091970. View

18.

Fenton R, Poulsen S, de la Mora Chavez S, Soleimani M, Busslinger M, Dominguez Rieg J . Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3. Am J Physiol Renal Physiol. 2015; 308(12):F1409-20. PMC: 4587593. DOI: 10.1152/ajprenal.00129.2015. View

19.

Thomas M, Moran J, Forsblom C, Harjutsalo V, Thorn L, Ahola A . The association between dietary sodium intake, ESRD, and all-cause mortality in patients with type 1 diabetes. Diabetes Care. 2011; 34(4):861-6. PMC: 3064042. DOI: 10.2337/dc10-1722. View

20.

Mente A, ODonnell M, Rangarajan S, Dagenais G, Lear S, McQueen M . Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies. Lancet. 2016; 388(10043):465-75. DOI: 10.1016/S0140-6736(16)30467-6. View