Purinergic regulation of ENaC in the distal nephron

摘要 随意控制肾脏钠的转运使肾脏钠排泄与膳食钠摄入量相匹配。因为那 排泄会影响血压，肾钠转运紊乱在很多情况下会导致异常 血压。此外，正如我们从大多数利尿剂和许多肾小管疾病的阻断作用中了解到的那样 正常的肾脏钠转运会改变血压。肾钠排泄微调以应对 醛固酮敏感的远端肾单位(ASDN)中的激素信号。在ASDN内， 上皮性钠通道(ENaC)是钠重吸收的主要介质。因此，ENaC的调制 活动是钠排泄和血压的重要调节因素。ENAC作为最终效应器发挥作用 肾素-血管紧张素-醛固酮系统(RAAS)在血压控制中的作用。ENaC的得失 像RAAS一样，功能通过降低和增加肾脏钠来增加和降低血压 排泄物。新出现的证据支持，还有其他重要的生理信号 与RAAS并行发挥作用的通路，以微调ASDN中的ENaC活动。以前的R01资助 我的实验室的研究表明，远端肾单位固有的嘌呤能系统调节 ENAC活性通过顶膜代谢型P2Y2受体抑制旁分泌信号 主细胞。我们的发现表明，这个嘌呤能系统在数量上对调节很重要。 ENaC，也许因此，钠的排泄和血压。然而，后者只是猜测。 以间接和草率的方式进行了测试。类似于ENaC功能的增加，功能障碍 对ENaC的正常旁分泌嘌呤能抑制被预测会导致盐敏感性和血液中的增加 钠排泄不当所致的压力。相比之下，这一系统的激活预计将 促进钠排泄。这项重新提交试验中提出的研究的前提是抑制性嘌呤能 调节ENaC有助于微调肾脏钠排泄，从而调节血液 压力。这些研究将提供机械性的理解，并提供高度的翻译 通过测试以下三个目标来确定人类状况：1)确定ASDN中是否有针对性的干扰 嘌呤能信号增强ENaC活性，减少钠排泄，引起盐敏感； 确定靶向激活ASDN中的P2Y2受体信号是否增加钠的排泄和 在一定程度上减轻强制盐敏感性；以及3)确定抑制性嘌呤能信号是否重要 用于人类肾脏的ENaC调节。预计这些研究的完成将制定一项 有助于正常调节钠排泄的重要生理机制；以及当 功能障碍可能导致某些形式的盐敏感；并可能成为治疗的新靶点 血压升高的治疗。

Summary Discretionary control of renal Na+ transport matches renal Na+ excretion with dietary Na+ intake. Because Na+ excretion can influence blood pressure, disordered renal Na+ transport in many instances causes abnormal blood pressure. Moreover, as we know from the actions of most diuretics and many tubulopathies interdiction of normal renal Na+ transport changes blood pressure. Renal sodium excretion is fine-tuned in response to hormonal signaling in the aldosterone-sensitive distal nephron (ASDN). Within the ASDN, the activity of the epithelial Na+ channel, ENaC, is the principal mediator of Na+ reabsorption. Consequently, modulation of ENaC activity is an important regulator of Na+ excretion and blood pressure. ENaC functions as one final effector of the renin-angiotensin-aldosterone system (RAAS) during the control of blood pressure. Gain and loss of ENaC function, like RAAS, increases and decreases blood pressure by decreasing and increasing renal Na+ excretion, respectively. Emerging evidence supports that there are other physiologically important signaling pathways that function in parallel with the RAAS to fine-tune ENaC activity in the ASDN. Previous R01 funded research from my laboratory demonstrated that a purinergic system intrinsic to the distal nephron regulates ENaC activity through inhibitory paracrine signaling via apical membrane metabotropic P2Y2 receptors in principal cells. Our findings have shown that this purinergic system is quantitatively important to the regulation of ENaC and perhaps consequently, sodium excretion and blood pressure. The latter, though, is only surmised having been tested indirectly and in a cursory manner. Similar to a gain of ENaC function, dysfunction of normal paracrine purinergic inhibition of ENaC is predicted to cause salt-sensitivity and increases in blood pressure as a result of inappropriate Na+ excretion. In contrast, activation of this system is predicted to promote Na+ excretion. The studies proposed in this resubmission test the premise that inhibitory purinergic regulation of ENaC contributes to the fine-tuning of renal Na+ excretion and consequently, regulation of blood pressure. These studies will provide mechanistic understanding and offer a high degree of translation to the human condition by testing the following three aims: 1) Determine if targeted disruption in the ASDN of purinergic signaling increases ENaC activity, decreases Na+ excretion and causes salt-sensitivity; 2) Determine if targeted activation of P2Y2 receptor signaling in the ASDN increases Na+ excretion and can mitigate to some degree forced salt-sensitivity; and 3) Determine if inhibitory purinergic signaling is important for ENaC regulation in the human kidney. It is expected that completion of these studies will elaborate a physiologically important mechanism that contributes to the normal regulation of Na+ excretion; and that when dysfunctional may cause certain forms of salt-sensitivity; and possibly serve as a novel therapeutic target for the treatment of elevated blood pressure.