Purinergic regulation of ENaC in the distal nephron

远端肾单位 ENaC 的嘌呤能调节

• 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
• 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

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.

总结 肾脏Na+转运的自由裁量控制使肾脏Na+排泄与饮食Na+摄入相匹配。因为Na+ 排泄可以影响血压，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变的作用中所知， 正常肾脏Na+转运的改变血压。肾钠排泄是微调， 醛固酮敏感性远端肾单位（ASDN）中的激素信号传导。在ASDN中， 上皮Na+通道ENaC是Na+重吸收的主要介质。因此，ENaC的调节 活性是Na+排泄和血压的重要调节剂。ENaC作为一个最终效应子， 在血压控制过程中的肾素-血管紧张素-醛固酮系统（RAAS）。ENaC损益 功能，如RAAS，通过减少和增加肾脏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生理上重要的信号 与RAAS平行发挥作用的途径，以微调ASDN中的ENaC活性。前一个R 01供资 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P2 Y2受体抑制旁分泌信号传导的ENaC活性 主要细胞我们的研究结果表明，这种嘌呤能系统是定量的重要的调节， ENaC，可能因此，钠排泄和血压。然而，后者只是猜测， 已经被间接地和粗略地测试过了。类似于ENaC功能的获得， 预测ENaC的正常旁分泌嘌呤能抑制会引起盐敏感性和血液中 压力是由于不适当的Na+排泄。相反，该系统的激活预计将 促进Na+排泄。在这次重新提交的研究中提出的假设是，抑制性嘌呤能 ENaC的调节有助于肾Na+排泄的微调，从而调节血液 压力这些研究将提供机械的理解，并提供高度的翻译， 通过测试以下三个目标来评估人类状况：1）确定是否有针对性地破坏ASDN， 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P2 Y2受体信号传导的靶向激活是否增加Na+排泄， 在一定程度上减轻强迫盐敏感性;和3）确定抑制性嘌呤能信号传导是否重要 用于人体肾脏中的ENaC调节。预计完成这些研究后， 生理上重要的机制，有助于正常调节Na+排泄;当 功能障碍可能导致某些形式的盐敏感性;并可能作为一种新的治疗靶点， 高血压的治疗

项目成果

Cellular and Molecular Mechanisms Regulating the Normal Physiological Function of the Epithelial Sodium Channel.

调节上皮钠通道正常生理功能的细胞和分子机制。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: AbdEl-Aziz,TarekM;Soares,Antonio;Mironova,Elena;Stockand,James
• 通讯作者: Stockand,James

Advances in venomics: Modern separation techniques and mass spectrometry.

• DOI: 10.1016/j.jchromb.2020.122352
• 发表时间: 2020-12-01
• 期刊: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
• 作者: Abd El-Aziz TM;Soares AG;Stockand JD
• 通讯作者: Stockand JD

Human recombinant soluble ACE2 (hrsACE2) shows promise for treating severe COVID-19.

• DOI: 10.1038/s41392-020-00374-6
• 发表时间: 2020-11-03
• 期刊: Signal transduction and targeted therapy
• 影响因子: 39.3
• 作者: Abd El-Aziz TM;Al-Sabi A;Stockand JD
• 通讯作者: Stockand JD