胃泌素及其受体在盐敏感性高血压发病机制中的研究

Gastrin, a peptide hormone secreted primarily by G-cells in the stomach and duodenum, acts on its receptor, the cholecystokinin B receptor (CCKBR), not only to regulate gastric acid secretion and oxyntic gland proliferation, but also to exert physiological actions outside of the gastric mucosa, including the kidney and so on. According to our preliminary study on gastrin and hypertension via clinical investigation and mouse models, we hypothesize that the renal gastrin system is involved in the regulation of blood pressure, possibly via sodium and water balance, and/or the renal dopamine system. However, the mechanism of the regulation is still unclear. Firstly, we will use CCKBR gene knock out mice and wild types accordingly, BALB/c mice and C57BL/6 mice, renal tubule cells of BALB/c mice, via In Vivo and In Vitro studies, to explore the regulation of gastrin and CCKBR to renal sodium transporters, renin-angiotensin system, renal dopamine system, sodium excretion and body blood pressures. Meanwhile, a case control study with clinical investigation will be performed to check the salt-sensitivity among hypertensive and normaltensive adults. The level of gastrin and other hormones in blood and urine will be tested. The polymorphism and mRNA levels analysis of CCKBR and related genes in blood cells and renal tubule cells will be conducted. We will combine the pathophysiology and genetic component to find the mechanism of salt-sensitive hypertension regulated by gastin system, and possible biomarkers for quick diagnosis of salt-sensitive hypertension, so as to provide important references for treatment and prevention of essential hypertension.

胃泌素作为一种重要的胃肠激素，除调节胃肠道的分泌功能外，还通过其受体对肾脏等有重要的生理调节作用。我们通过初期人群临床调查研究和动物试验结果推测，胃泌素通过其受体直接调节肾脏钠水代谢，或通过肾脏多巴胺系统等在盐敏感性高血压的发病中具有重要作用。为了探索其调节机制，本研究首先利用胃泌素受体基因敲除和野生型小鼠、BALB/c小鼠和C57BL/6小鼠、小鼠肾脏小管细胞，研究胃泌素及其受体在对肾脏钠水代谢和血压调节中的分子机制，以及对肾脏多巴胺系统和肾素血管紧张素系统的相互作用等；同时，通过人体盐敏感性试验，检测盐敏感性和非盐敏感性高血压和正常人群的血液和尿液中胃泌素等激素水平、血细胞和肾脏小管细胞中胃泌素受体及其相关基因的突变和mRNA水平的差异。通过综合分析，研究胃泌素系统在盐敏感性高血压中的发病机制，探索盐敏感性高血压快速诊断的可能分子标志物，为高血压的预防和治疗提供依据。

胃泌素作为一种重要的胃肠激素，除调节胃肠道的分泌功能外，还通过其受体对大肠、胰腺、小肠、肝脏、肾脏等有重要的生理调节作用。我们通过初期人群临床调查研究和动物试验结果推测，胃泌素通过其受体，可能直接，或/和间接通过肾素-血管紧张素系统、肾脏多巴胺系统，调节肾脏钠水代谢，在盐敏感性高血压的发病中具有重要的调节作用。为了探索其调节机制，本课题首先利用胃泌素受体基因敲除小鼠(CCKBR-/-)、胃泌素敲除小鼠（Gast-/-）、多巴胺D5受体基因敲除小鼠(D5R-/-)、BALB/c小鼠和C57BL/6小鼠，研究胃泌素及其受体在对肾脏钠水代谢和血压调节中的分子机制；同时，通过人体盐敏感性试验，检测盐敏感性和非盐敏感性高血压和正常人群的血液中胃泌素等激素水平，探索盐敏感性高血压新的发病机制。研究发现包括：1）多巴胺D5受体和胃泌素CCKB受体在肾脏近曲小管能够协同作用调节机体钠水代谢维持机体血压的平衡；2）胃泌素通过小管细胞膜LAT（L-type amino acid transporter）诱导肾脏近曲小管增加L-DOPA的摄取，进而促进多巴胺的合成，从而调节机体血压；3）胃泌素可能通过调节肾脏肾脏NHE3、NKCC、βeNaC、γeNaC和αNKA钠离子通道蛋白调节机体血压；4）同时，进一步探索发现，胃泌素能够通过抑制小肠NHE3的活性抑制钠的吸收而抑制盐敏感性高血压，但具体机制还有待于进一步研究。该研究为盐敏感性高血压的预防和治疗提供了新的策略和理论依据。