肾近端小管钠氢交换因子3在血管紧张素Ⅱ依赖性高血压中的作用机制研究进展

Research progress on the mechanism of kidney proximal tubule NHE3 in the angiotensinⅡ-dependent hypertension

高血压是一种涉及遗传易感性、神经内分泌失调、心血管和肾功能障碍以及饮食因素的多因素疾病。对人正常血压稳态和高血压发展的贡献因素或机制中,焦点集中在钠(Na^(+))摄入量和盐敏感性。临床、流行病学和遗传动物模型的研究显示,Na^(+)摄入量与血压稳态密切相关,而过量的Na^(+)摄入在黑人、老年人和患有慢性肾病的人群中与血压升高关系较为密切。Na^(+)摄入和排泄的平衡由胃肠道小肠和肾近端和远端小管来协调。Na^(+)氢(H^(+))交换因子3(NHE3),即溶质载体家族9成员3(SLC9A3),在小肠和肾脏的近端小管中介导主动的跨细胞钠和碳酸氢盐的重吸收发挥了关键作用。然而,小肠和肾近端小管NHE3在正常血压稳态和高血压发病机制中的作用尚未清楚。最近,本课题组使用新型基因修饰全身、肾脏、近端小管特异性NHE3敲除小鼠模型,探讨了肠道和肾近端小管NHE3在维持基础血压稳态和在血管紧张素Ⅱ诱导高血压发展中的关键作用和潜在机制。这些新发现不仅支持了小肠和肾近端小管NHE3在维持正常血压以及在血管紧张素Ⅱ依赖性高血压发展中发挥的关键作用,同时还可能为治疗人类难控制性高血压提供潜在的新的治疗靶点。

Hypertension is a multifactorial disorder involving genetic susceptibility,neuroendocrine dysregulation,cardiovascular and kidney dysfunction,and dietary factors.One of the most studied factors contributing to normal blood pressure control and the development of hypertension is sodium(Na^(+))intake and salt sensitivity.Studies in clinical,epidemiological,and genetic animal models have shown a close relationship between Na^(+)intake and blood pressure,with excessive Na^(+)intake particularly associated with hypertension in blacks,elderly and those with chronic kidney disease.The balance between Na^(+)intake and excretion is primarily regulated by small intestines of the gastrointestinal tract and the proximal and distal tubules of kidneys.The Na^(+)and hydrogen(H^(+))exchanger 3(NHE3),member 3 of solute carrier family 9(SLC9A3),plays a crucial role in mediating active transcellular Na^(+)and bicarbonate reabsorption in the proximal tubules of the small intestine and kidneys.However,the role and mechanism of NHE3 in small intestines and proximal tubules of the kidneys in normal blood pressure regulation and the pathogenesis of hypertension have not been well studied.Recently,the research group of this project utilized novel genetically modified whole-body,kidney,and proximal tubule-specific NHE3 knockout mouse models to investigate the critical role and mechanisms of intestinal and kidney proximal tubular NHE3 in maintaining basal blood pressure homeostasis and in the development of angiotensinⅡ-induced hypertension.These new findings not only support the critical roles of intestinal and kidney proximal tubular NHE3 in maintaining normal blood pressure and in the development of angiotensinⅡ-dependent hypertension,but also provide potential new therapeutic targets for treating poorly controlled hypertension in humans.