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/flvillin-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/flvillin-Cre mice and Dahl salt-sensitive rats than their respective controls, Cckbr^fl/flvillin 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.

中文翻译：

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肠胃泌素/CCKBR（胆囊收缩素 B 受体）通过 PKC（蛋白激酶 C）介导的 NHERF1 和 NHERF2 通路抑制肠 Na+/H+ 交换剂 3 活性来改善盐敏感性高血压

背景：本研究直接测试了肠道胃泌素/CCKBR（胆囊收缩素B受体）在盐敏感性高血压治疗中的关键作用。方法：成年肠道特异性Cckbr基因敲除小鼠（Cckbr ^fl/fl villin-Cre）和Dahl研究了盐敏感大鼠高盐摄入量（8% NaCl，6-7 周）对肠道 Na ^+/ H ⁺交换剂 3 表达、尿钠浓度和血压的影响。高盐饮食在Cckbr ^fl/fl villin-Cre小鼠和 Dahl 盐敏感大鼠中比其各自的对照Cckbr ^fl/fl在更大程度上增加了尿钠浓度和收缩压vilin小鼠和 SS13 ^BN大鼠。我们构建了胃泌素-SiO ₂微球，使胃泌素能够特异性和选择性地刺激肠道CCKBR，而不会将其吸收到循环中。结果：胃泌素-SiO _{2微球治疗通过抑制肠道Na} ⁺预防高盐性高血压和尿钠浓度增加^/ H ⁺交换器 3 贩运和活动，增加大便钠而不致腹泻。胃泌素介导的肠道 Na ^{+ /} H ^+抑制交换器 3 的活性，与 PKC（蛋白激酶 C）介导的 NHERF1 和 NHERF2 活化有关。结论：这些结果支持肠胃泌素/CCKBR 在降低肠钠吸收和保持血压在正常范围内的关键作用。胃泌素-SiO ₂微球的胃肠道给药是一种治疗盐敏感性高血压且无副作用的有前途且安全的策略。