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.
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.
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DOI：
10.1161/hypertensionaha.121.18791
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发表时间：
2022-08
期刊：
影响因子：
8.3
通讯作者：
Yang, Zhiwei
中科院分区：
文献类型：
--
作者：
Jiang, Xiaoliang;Liu, Yunpeng;Zhang, Xin-Yang;Liu, Xue;Liu, Xing;Wu, Xianxian;Jose, Pedro A.;Duan, Shun;Xu, Fu-Jian;Yang, Zhiwei
本研究直接检测了肠胃泌素/胆囊收缩素B受体（CCKBR）在盐敏感性高血压治疗中的关键作用。研究了高盐摄入（8%NaCl，6-7周）对肠Na+/H+交换器3表达、尿钠浓度和血压的影响，成年的精氨酸特异性Cckbr敲除小鼠（Cckbrfl/fl villin-Cre）和Dahl盐敏感大鼠。高盐饮食增加尿钠浓度和收缩压在更大程度上在Cckbrfl/fl villin-Cre小鼠和Dahl盐敏感大鼠比各自的控制，Cckbrfl/fl villin小鼠和SS 13 BN大鼠。我们构建了胃泌素-SiO2微球，使胃泌素能够特异性和选择性地刺激肠道CCKBR，而不吸收到循环中。胃泌素-SiO2微球治疗通过抑制肠道Na+/H+交换体3的运输和活性，增加粪便钠而不引起腹泻，从而防止高盐诱导的高血压和尿钠浓度增加。胃泌素介导的肠Na+/H+交换器3活性抑制，与PKC（蛋白激酶C）介导的NHERF 1和NHERF 2激活相关。这些结果支持肠胃泌素/CCK BR在减少肠钠吸收和保持血压在正常范围内的关键作用。胃肠道给药胃泌素-SiO2微球是一种有前途的和安全的策略，治疗盐敏感性高血压，没有副作用。
The present study directly tested the crucial role of intestinal gastrin/CCKBR (cholecystokinin B receptor) in the treatment of salt-sensitive hypertension. 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. 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. 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.
影响因子：
2.7
作者：
Ashurst, H. Louise;Varro, Andrea;Dimaline, Rod
通讯作者：
Dimaline, Rod