Purinergic regulation of ENaC in the distal nephron

远端肾单位 ENaC 的嘌呤能调节

基本信息

批准号：
10132733
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132733
关键词：
Agonist Aldosterone Automobile Driving Biological Assay Blood Pressure Cells Consumption DOCA 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 dietary 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

项目摘要

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+ 转运的酌情控制使肾脏 Na+ 排泄与膳食 Na+ 摄入量相匹配。因为钠+ 排泄会影响血压，肾脏 Na+ 转运紊乱在许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病的作用中了解到的那样正常肾脏 Na+ 转运的改变会改变血压。肾钠排泄根据以下因素进行微调醛固酮敏感的远端肾单位 (ASDN) 中的激素信号传导。在 ASDN 内，上皮Na+通道ENaC是Na+重吸收的主要介质。因此，ENaC 的调制活性是Na+排泄和血压的重要调节剂。 ENaC 作为最终效应器之一肾素-血管紧张素-醛固酮系统（RAAS）在血压控制过程中的作用。 ENaC 的增益和损失功能，如 RAAS，通过减少和增加肾 Na+ 来增加和降低血压分别排泄。新出现的证据支持还有其他重要的生理信号传导与 RAAS 并行发挥作用的途径可微调 ASDN 中的 ENaC 活性。以前的 R01 资助我实验室的研究表明，远端肾单位固有的嘌呤能系统调节通过顶膜代谢型 P2Y2 受体抑制旁分泌信号传导的 ENaC 活性主细胞。我们的研究结果表明，这种嘌呤能系统对于调节在数量上很重要 ENaC 的影响，或许因此影响钠排泄和血压。但后者只是推测经过间接和粗略的测试。与 ENaC 功能的获得类似， ENaC 的正常旁分泌嘌呤能抑制预计会导致盐敏感性和血液增加由于 Na+ 排泄不当导致的压力。相反，预计该系统的激活将促进Na+排泄。本次重新提交测试中提出的研究的前提是抑制性嘌呤能 ENaC 的调节有助于微调肾 Na+ 排泄，从而调节血液压力。这些研究将提供机制上的理解，并为通过测试以下三个目标来评估人类状况： 1) 确定 ASDN 中是否有针对性的破坏嘌呤能信号增加 ENaC 活性，减少 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+ 排泄并可以在一定程度上减轻强迫盐敏感性； 3) 确定抑制性嘌呤能信号传导是否重要用于人肾中的 ENaC 调节。预计这些研究的完成将详细阐述有助于正常调节 Na+ 排泄的重要生理机制；当功能失调可能会导致某些形式的盐敏感性；并可能作为新的治疗靶点高血压的治疗。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comparative study of the in vivo toxicity and pathophysiology of envenomation by three medically important Egyptian snake venoms.

三种医学上重要的埃及蛇毒的体内毒性和毒液病理生理学的比较研究。

DOI：
发表时间：
2020
期刊：
影响因子：
6.1
作者：
Abd El;Shoulkamy, Mahmoud I;Hegazy, Ahmed M;Stockand, James D;Mahmoud, Ahmed;Mashaly, Ashraf M A
通讯作者：
Mashaly, Ashraf M A

Advances in venomics: Modern separation techniques and mass spectrometry.

毒液学的进展：现代分离技术和质谱法。