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Regulation of K+ balance by distal nephron TRPV4 channel

远端肾单位 TRPV4 通道对 K 平衡的调节

基本信息

批准号：
10203950
负责人：
Oleh Pochynyuk
金额：
$ 34.65万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2018-09-18 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203950
关键词：
Acid-Base Equilibrium Address Animal Model Animals Arrhythmia Cardiovascular system Cells Chronic Kidney Failure Clinical Development Diet Dietary Potassium Distal Duct (organ) structure Electrolytes Electrophysiology (science)Epithelial Cells Equilibrium Excretory function Fruit Functional disorder Genetic H(+)-K(+)-Exchanging ATPase Homeostasis Human Hyperaldosteronism Hypokalemia Image Ingestion Intake Kidney Life Maintenance Measurement Mediating Microscopy Molecular Monitor Mus Muscle Nephrons Neurons Osmolar Concentration Pathology Permeability Pharmacology Physiological Physiology Potassium Process Publishing Regimen Regulation Renal function Rodent Role Scheme Signal Transduction Site Testing Tissues Tubular formation Urine Vanilloid Variant Water base cardiovascular health dietary manipulation extracellular genetic manipulation hyperkalemia knockout animal large-conductance calcium-activated potassium channels novel strategies patch clamp receptor recruit response urinary

项目摘要

SUMMARY Tight regulation of K+ balance is fundamental for normal physiology. Disturbed K+ homeostasis is associated with a wide spectrum of cardiovascular- and kidney-related pathologies. The distal nephron (DN), including the connecting tubule (CNT) and the collecting duct (CD), is the major site of controlled potassium transport in the kidney, which is essential to match urinary K+ excretion to varying dietary K+ intake. In this proposal, we posit that the mechanosensitive Ca2+-permeable TRPV4 channel abundantly expressed in the DN is a critical determinant of renal potassium handling capable of stimulating flow-dependent K+ secretion via maxi-K (BK) channel and inhibiting H+-K+ ATPase-dependent K+ reabsorption. We generated abundant supportive evidence that the TRPV4 activity in the DN is regulated by dietary potassium intake with its dysfunction causing significant distortions of systemic K+ balance. TRPV4 -/- mice have a markedly reduced BK channel activity in the DN and develop hyperkalemia when dietary potassium intake is high. On the contrary, TRPV4 deletion augments H+-K+ ATPase activity and protects against hypokalemia when dietary potassium intake is low. Overall, we hypothesize that TRPV4 serves as a physiologically relevant kaliuretic factor during adaptations to dietary potassium regimen by stimulating BK-mediated K+ secretion and inhibiting H+-K+ ATPase-dependent K+ reabsorption. To address this central hypothesis, we developed three specific aims: SA1: Examine molecular and signaling determinants of TRPV4 regulation in the DN by dietary K+ intake. SA2: Establish the importance of TRPV4 function for BK-mediated K+ secretion in the DN and define pathophysiological ramifications of its disruption on systemic K+ balance. SA3: Explore the mechanism and relevance of regulation of K+ reabsorption in the DN by TRPV4. To bring this project to fruition, we recruit strong collaborative expertise and implement a comprehensive experimental arsenal which involves monitoring TRPV4 and BK channels activity with patch clamp electrophysiology, intracellular Ca2+ and H+-K+ ATPase-mediated pH measurements, confocal immunofluorescent microscopy in native DN cells of rodents and humans, balance studies upon manipulation of dietary K+ intake in conventional and genetically manipulated animals. Overall, we expect to directly demonstrate the physiological relevance of mechanosensitive TRPV4 channel in the DN at the systemic level and will define pathophysiological ramifications of TRPV4 dysfunction on systemic K+ homeostasis. Furthermore, this will urge development of novel strategies based on targeting TRPV4 to manage life-threatening states of hyper- and hypokalemia in clinical setting.

总结