Purinergic regulation of ENaC in the distal nephron

远端肾单位 ENaC 的嘌呤能调节

• 批准号: 9899746
• 负责人: James D Stockand
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899746
• 关键词: Agonist; Aldosterone; Automobile Driving; Biological Assay; Blood Pressure; Cells; Consumption; DOCA; Diet; Disease; Distal; Diuretics; Electrophysiology (science); Environment; Excretory function; Feedback; Functional disorder; Funding; Genes; Human; Intake; Kidney; Kidney Diseases; Knockout Mice; Laboratories; Measurement; Mediator of activation protein; Membrane; Metabolic; Modeling; Molecular Genetics; Mus; Natriuresis; Nephrons; P2Y2 receptor; Paracrine Communication; Pharmacology; Phenocopy; Phenotype; Physiological; Receptor Signaling; Refractory; Regulation; Renin; Renin-Angiotensin-Aldosterone System; Research; Signal Pathway; Signal Transduction; Sodium; Sodium Chloride; System; Tamoxifen; Telemetry; Testing; Transgenic Mice; Urinalysis; Urine; Water-Electrolyte Balance; apical membrane; blood pressure regulation; designer receptors exclusively activated by designer drugs; epithelial Na+ channel; experimental study; gain of function; hormonal signals; loss of function; luminal membrane; mouse model; new therapeutic target; novel; overexpression; paracrine; patch clamp; pressure; receptor; response; salt sensitive; translation to humans; urinary

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.

概括 肾脏NA+转运的自由控制与肾脏Na+排泄与饮食NA+摄入量相匹配。因为na+ 排泄物会影响血压，在许多情况下导致异常的肾脏Na+转运无序 血压。此外，正如我们从大多数利尿剂和许多肾小管病的动作中所知道的那样 正常的肾脏Na+转运会改变血压。肾脏排泄响应于 醛固酮敏感远端肾单位（ASDN）中的激素信号传导。在ASDN中， 上皮Na+通道ENAC是Na+重吸收的主要介体。因此，调节ENAC 活性是Na+排泄和血压的重要调节剂。 ENAC充当最终效应因子 在控制血压期间，肾素 - 血管紧张素 - 醛固酮系统（RAAS）。增益和损失ENAC 像RAAS这样的功能通过降低和增加肾脏Na+来增加和降低血压 分别排泄。新兴证据支持还有其他重要的生理信号传导 与RAA并行发挥作用的途径，可在ASDN中微调ENAC活性。先前的R01资助 我实验室的研究表明，尖齿系统的固有源是远端肾脏的调节 通过抑制性旁分泌信号通过顶膜代谢P2Y2受体通过抑制性旁分泌信号传导的ENAC活性 主要细胞。我们的发现表明，这种嘌呤能系统对调节很重要 ENAC，也许因此是钠排泄和血压。但是，后者只被推测 通过间接和粗略地进行了测试。类似于ENAC功能的增长，功能障碍 预计正常的旁分泌嘌呤能抑制ENAC会引起盐的敏感性，并增加血液 由于不适当的Na+排泄而导致的压力。相反，该系统的激活预计 促进Na+排泄。在此重新提取的前提中提出的研究是抑制性嘌呤能的前提 ENAC的调节有助于肾脏Na+排泄的微调，因此，血液调节 压力。这些研究将提供机械理解，并为 通过测试以下三个目的通过测试人类状况：1）确定是否针对ASDN的目标破坏 嘌呤能信号会增加ENAC活性，降低Na+排泄并引起盐敏感性。 2） 确定ASDN中P2Y2受体信号传导的靶向激活是否会增加Na+排泄，并且可以 在某种程度上缓解强制盐敏感性； 3）确定抑制性嘌呤能信号是否重要 用于人类肾脏中的ENAC调节。预计这些研究的完成将详细说明 生理上重要的机制，有助于Na+排泄的正常调节；那时 功能失调可能引起某些形式的盐敏感性；并可能充当新型的治疗靶点 血压升高的治疗。