胃肠-肾脏尿钠排泄轴在高血压病发生中的作用和机制研究

基于“口服NaCl比等量静脉输注诱发更多尿钠排泄量”的现象，以及胃泌素利尿作用，我们提出“胃肠-肾脏尿钠排泄轴”设想。既往研究发现高盐饮食胃泌素分泌增加；肾脏胃泌素、多巴胺受体间存在协同利尿作用，二者缺一不可。高血压状态下，不仅胃肠道钠盐感知受体功能下降、胃泌素/多巴胺受体交互作用也丧失。鉴于“多巴胺、胃泌素受体”均为G蛋白偶联受体，其磷酸化受到GRK4调节。GRK4功能增强损害这些受体功能；抑制高血压大鼠GRK4则降低血压、恢复这些受体功能；我们推测：①刺激胃肠钠盐感知受体引起胃肠激素分泌；胃肠激素和肾脏激素受体通过交互作用调控尿钠排泄。②高血压状态下，胃肠道钠盐感知受体功能下降；胃肠和肾脏激素受体利尿作用下降，它们的交互作用也发生异常，致尿钠排泄障碍。③GRK4活性增高导致胃肠-肾脏尿钠排泄轴异常，对GRK4干预有望成为恢复胃肠-肾脏尿钠排泄轴功能、降低高血压的重要手段。

Oral NaCl produces stronger natriuresis than intravenous infusion of same amount NaCl. Due to the natriuretic effects of gastrin,we proposed there is gastro-renal axis,which is involved in hypertension. Our previous studies found the increased levels of plasma gastrin after high-salt diet and the synergistic interaction between renal gastrin and dopamine receptors. In the hypertensive states, the sensitivity of salt sensing receptor is lowered,the gastrin/dopamine receptor interaction is lost. Both gastrin and dopamine receptor belong to G protein coupled receptor family,whose phosphorylation is regulated by GRK4.The hyper-activity of GRK4 causes the dysfunction of dopamine and gastrin receptors,which are reversed by inhibition of GRK4. We hypothesize that 1)Stimulation of salt-sensing receptor induces secretion of gastric hormones,there are interactions between renal gastrin hormone receptors and renal endocrine hormone receptors,which synergistically induce sodium excretion.2)In hypertensive states,the sensitivity of gastric salt sensing receptor is decreased,the interactions of gastric hormone receptors and renal endocrine hormone receptors are lost,leading to impaired sodium excretion and hypertension.3)The hyper-activity of GRK4 leads to abnormal function of gastro-renal axis, intervention of GRK4 might be helpful to normalize abnormal gastro-renal axis,normalize the renal function and lower blood pressure.