Role of PON3 in regulating renal Na+ and K+ homeostasis

PON3 在调节肾钠钾稳态中的作用

基本信息

批准号：
10338835
负责人：
Shujie Shi
金额：
$ 31.3万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338835
关键词：
Address Affect Aldosterone Amiloride Antihypertensive Agents Apical Arylesterase Biological Models Biotinylation Blood Blood Pressure Caenorhabditis elegans Cells Data Diet Dietary Potassium Distal Distal convoluted renal tubule structure Duct (organ) structure Endoplasmic Reticulum Extracellular Fluid Family Genetic Transcription Homeostasis Hypertension Immunoblotting Immunofluorescence Immunologic Intake Intercalated Cell Ion Channel Kidney Knockout Mice Measures Mediating Metabolic Molecular Chaperones Monitor Mus Natriuresis Nephrons Neurons Patch-Clamp Techniques Pathway interactions Pattern Phosphorylation Physiological Potassium Potassium Channel Property Proteins Publishing Radio Rattus Regional Perfusion Regulation Renal function Role SLC12A3 gene Side Sodium Sodium Chloride Stains Structure Substrate Specificity Surface Telemetry Tissues Touch sensation Ubiquitination Water Work absorption aryldialkylphosphatase base blood pressure regulation cell type dietary salt differential expression driving force epithelial Na+ channel extracellular hyperkalemia in vivo large-conductance calcium-activated potassium channels member multicatalytic endopeptidase complex new therapeutic target novel receptor

项目摘要

ABSTRACT The mammalian paraoxonase (PON) family consists of three highly conserved members (PON1, PON2 and PON3) with unique anti-oxidative and anti-atherosclerotic properties. PON1 and 2 have been implicated in blood pressure (BP) regulation. While the role of PON3 in regulating BP has not been investigated, it is expressed in the aldosterone-sensitive distal nephron where the fine tuning of Na+ absorption and K+ secretion occurs. PONs share key structural and functional features with MEC-6, an endoplasmic reticulum-resident chaperone of C. elegans. MEC-6 is required for proper folding, assembly, and surface expression of the mechanosensitive degenerin channel in touch receptor neurons. The chaperon function is conserved between mammalian PONs and C. elegans MEC-6. We have previously shown that both PON2 and PON3 regulate functional expression of the epithelial Na+ channel (ENaC), a member of the ENaC/degenerin family of ion channels. ENaC mediates the rate-limiting step of Na+ reabsorption in distal nephron and has a key role in volume and BP control. While the constitutive K+ secretion is conducted by the renal outer medullary K+ (ROMK) channels, ENaC-dependent and flow-induced K+ secretion is mediated by the large conductance K+ (BK) channels. In the preliminary studies, we found that Pon3 KO mice have higher ENaC activity and enhanced amiloride-sensitive natriuresis, suggesting ENaC functional expression is upregulated in the absence of PON3. In addition, we have identified BK channel as a novel target of PON3. When expressed in HEK293 cells, PON3 interacted with BK α subunit to reduce its surface expression and channel activity. Our proposed studies will define mechanisms by which PON3 functions as a chaperone in the regulation of ENaC and BK expression. We will determine the consequences of deleting PON3 in renal Na+ and K+ handling and BP control in mice. Successful completion our proposed studies will enhance our understanding of the mechanisms by which PONs function as chaperones and their physiological roles in kidney function and BP control.

抽象的哺乳动物对氧磷酶 (PON) 家族由三个高度保守的成员组成（PON1、 PON2和PON3）具有独特的抗氧化和抗动脉粥样硬化特性。与血压 (BP) 调节有关，而 PON3 在调节血压中的作用。尚未进行研究，它在醛固酮敏感的远端肾单位中表达，其中 Na+ 吸收和 K+ 分泌的微调具有相同的关键结构和功能。 MEC-6 的特征是 MEC-6 的内质网驻留伴侣。机械敏感的退化蛋白的正确折叠、组装和表面表达所需的触摸受体神经元中的通道在哺乳动物之间是保守的。 PON 和线虫 MEC-6 我们之前已经表明 PON2 和 PON3 都可以调节。上皮 Na+ 通道 (ENaC) 的功能表达，ENaC/degenerin 的成员 ENaC 离子通道家族介导远端肾单位 Na+ 重吸收的限速步骤。并在容量和血压控制中发挥关键作用，而组成型 K+ 分泌则由其进行。肾外髓 K+ (ROMK) 通道、ENaC 依赖性和流量诱导的 K+ 分泌是由大电导 K+ (BK) 通道介导的。在初步研究中，我们发现。 Pon3 KO 小鼠具有更高的 ENaC 活性和增强的阿米洛利敏感性尿钠排泄，表明 ENaC 功能表达在 PON3 缺失的情况下上调。已经确定 BK 通道是 PON3 的新靶标，当在 HEK293 细胞中表达时，PON3。与 BK α 亚基相互作用以减少其表面表达和通道活性。研究将确定 PON3 在调节中作为伴侣的机制我们将确定删除肾 Na+ 中 PON3 的后果。小鼠中 K+ 处理和血压控制的成功完成将增强我们提出的研究。我们对 PON 作为伴侣的机制的理解及其在肾功能和血压控制中的生理作用。