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 (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-SiO(2) microspheres to enable gastrin to stimulate specifically and selectively intestinal CCKBR without its absorption into the circulation. RESULTS: Gastrin-SiO(2) 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-SiO(2) microspheres is a promising and safe strategy to treat salt-sensitive hypertension without side effects.