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.

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 Cckbr-knockout mice (Cckbrfl/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 Cckbrfl/fl villin-Cre mice and Dahl salt-sensitive rats than their respective controls, Cckbrfl/fl villin mice and SS13BN 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.

• Authors: Xiaoliang Jiang, Yunpeng Liu, Xin-Yang Zhang, Xue Liu, Xing Liu, Xianxian Wu, Pedro A Jose, Shun Duan, Fu-Jian Xu, Zhiwei Yang
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 79 Issue 8 Pg. 1668-1679 (08 2022) ISSN: 1524-4563 [Electronic] United States
• PMID: 35674015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Gastrins
• Phosphoproteins
• Receptor, Cholecystokinin B
• Slc9a3r2 protein, rat
• Sodium Chloride, Dietary
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers
• sodium-hydrogen exchanger regulatory factor
• Sodium Chloride
• Silicon Dioxide
• Sodium
• Protein Kinase C

Topics

• Animals
• Gastrins (metabolism)
• Hypertension
• Intestines
• Mice
• Phosphoproteins
• Protein Kinase C (metabolism)
• Rats
• Rats, Inbred Dahl
• Receptor, Cholecystokinin B (genetics, metabolism)
• Silicon Dioxide (metabolism)
• Sodium (metabolism)
• Sodium Chloride (metabolism)
• Sodium Chloride, Dietary (metabolism)
• Sodium-Hydrogen Exchanger 3
• Sodium-Hydrogen Exchangers