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.

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.