激活TRPV1调控高盐负荷下肾集合管上皮细胞钠重吸收的机制

High salt intake is closely related to the risks of hypertension. Epithelial Na+ channel (ENaC) in kidney collecting ducts is critical for urinary sodium reabsorption. ENaC function is enhanced by long-term high-salt load through activation of rennin-angiotensin-aldostone system (RAAS).Salt restriction and diuretics are the main interventions against high-salt intake. However, it is not clear whether dietary supplements promote urinary sodium excretion. Our recent study found that long-term high-salt diet increased blood pressure and vascular oxidative stress in wild type mice. Dietary capsaicin intervention promoted urinary sodium excretion and reduced blood pressure. However, capsaicin had no effect on TRPV1 (capsaicin receptor) knockout mice, Thus, we suppose that dietary capsaicin regulates ENaC and its related signal pathways and promotes urinary sodium excretion through TRPV1 activation. In vivo and in vitro,this study will elucidate the mechanisms by which TRPV1 regulates ENaC and inhibits high-salt induced oxidative stress in kidney collecting ducts, explore whether WNK1-SPAK/OSR1 and MR-SGK1 pathways are involved in, reveal whether capsaicin ameliorates high-salt induced kidney impairment and improves urinary sodium excretion, and provide new strategy for hypertension prevention.

高血压与高盐摄入关系密切，肾集合管上皮细胞钠通道（ENaC）在尿钠重吸收中起重要作用。长期高盐负荷激活肾素血管紧张素系统及促进ENaC对钠的重吸收。限盐和利尿剂是目前干预高盐的主要措施，但膳食因子能否促进尿钠排泄不甚清楚。我们前期发现长期高盐摄入升高野生型小鼠血压及增加血管氧化应激，但予膳食辣椒素干预则可促进尿钠排泄及降低血压,而这种效应在辣椒素受体（TRPV1)敲除小鼠中缺失。为此，我们提出膳食辣椒素通过激活TRPV1调控肾集合管钠通道及其相关分子信号通路，促进尿钠排泄的假说。本研究拟在离体与整体水平阐明膳食辣椒素激活TRPV1调控ENaC等钠转运体和抑制高盐介导的肾小管氧化应激的机制，明确WNK1-SPAK/OSR1和/或MR-SGK1等信号通路是否参与,揭示膳食因子辣椒素能否作用于其特异靶点TRPV1拮抗高盐对肾脏的损害，并促进尿钠的排泄,为高血压防治提供新的干预策略。

高血压与高盐（钠）饮食关系密切， 肾集合管上皮细胞钠通道（ENaC）在尿钠重吸收中起重要作用。长期高盐负荷激活肾素血管紧张素系统及促进ENaC对钠的重吸收。限盐和利尿剂是目前干预高盐的主要措施，但膳食因子能否促进尿钠排泄不甚清楚。. 我们前期工作发现长期高盐摄入升高野生型小鼠血压及增加血管氧化应激，但予膳食辣椒素干预则可促进尿钠排泄及降低血压, 而这种效应在辣椒素受体（TRPV1)敲除小鼠中缺失， 因此推测TRPV1可能是肾脏钠的排泄中的靶点之一。在此基础上，本研究在离体与整体水平阐明膳食辣椒素激活TRPV1调控ENaC等钠转运体和抑制高盐介导的肾小管氧化应激，这种调控是通过WNK1-SPAK/OSR1和/或MR-SGK1等信号通路所介导继而促进尿钠排泄以降低血压。本研究证实高盐饮食时TRPV1表达或功能下降，钠通道活性增强，尿钠排泄失代偿，血压升高，TRPV1-/-小鼠表现更为明显；证实TRPV1参与调控钠通道活性，长期高盐饮食后尿钠排泄失代偿可能与TRPV1受损有关；激活TRPV1可通过Ca2+/PKA信号通路及减少氧化应激抑制WNK1-SPAK/OSR1-ENaC 和/或MR-SGK1- ENaC；证实TRPV1是调控肾脏集合管钠重吸收的重要靶点，添加膳食辣椒素可能有助于习惯高盐饮食人群对高血压的预防。