敲除TRPC6促进肾集合管钠重吸收致盐敏感高血压的机制

TRP通道调控细胞钙与高血压发生关系密切，细胞钙依赖的PKC通路与Na+/K+-ATP酶活性及肾集合管钠重吸收有关。我们发现高盐能上调集合管TRPC6表达，TRPC6敲除显著减少肾脏钠排泄及加重高盐导致的高血压，与上调肾集合管TRPC3和Na+/K+-ATP酶表达有关，但其机制不清楚。为此，我们提出假设“高盐激活肾集合管TRPC6介导细胞内Ca2+增加，激活AMPK/PKC信号通路，并负反馈抑制Na+/K+-ATP酶活性，减少Na+重吸收和转运，维持机体钠水平衡。TRPC6基因敲除可增强TRPC3介导线粒体钙异常致ROS生成增加，激活Na+/K+-ATP酶活性，增加Na+重吸收和转运，从而加重高盐导致的钠水潴留和血压升高。”研究拟从整体、细胞和分子水平揭示高盐激活TRPC6调控肾集合管Na+/K+-ATP酶及促进高盐诱导高血压的机制,为高血压的防治提供新的干预靶标。

The regulation of intracellualr calcium by transient receptor potential (TRP) channels is correlated with the pathogenesis of hypertension, while the calcium-dependent PKC pathway is correlated with the activity of Na+/K+-ATPase and the sodium reabsorption in the renal collecting duct (CD). We found that high salt (HS) treatment upregulated the expression levels of TRPC6, whereas TRPC6 knockout exhibits reduced renal sodium excretion and aggravates HS-induced hypertension, which is correlated with the upregualtions of TRPC3 and Na+/K+-ATPase in the renal CD, but the mechanism remains unclear yet. Therefore, we proposed the hypothesis that, HS treatment lead to activation of TRPC6 and an increase in intracellular Ca2+ in the CD, which result in AMPK/PKC activation, feedback inhibition of Na+/K+-ATPase, reduced Na+ reabsorption and maintained sodium-water balance. TRPC6-/- enhances TRPC3-mediated mitochondrial calcium dysfunction and ROS production, which further results in the activation of Na+/K+-ATPase, increased Na+ reabsorption and aggravated HS-induced sodium-water retention and hypertension. This study will illustrate the mechanism of TRPC6 in regulating the activity of Na+/K+-ATPase upon HS treatment and the role in salt-induced hypertension in the whole, cellular and molecular levels. Meanwhile, this study will help provide the new target for the prevention and treatment of hypertension.