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Regulation of Renal WNK Signaling in Intercalated Cells

闰细胞中肾脏 WNK 信号传导的调节

基本信息

批准号：
10440321
负责人：
AROHAN R SUBRAMANYA
金额：
$ 37.54万
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：
2019
资助国家：
美国
起止时间：
2019-07-23 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440321
关键词：
Affect Aldosterone Animals Apical Blood Bumetanide CUL3 gene Cell Culture Techniques Cell Separation Cells Chlorides Complex Coupled Data Defect Dietary Potassium Disease Distal Distal convoluted renal tubule structure Ensure Equilibrium Excretory function Exhibits Goals Health Homeostasis Hypokalemia In Vitro Intercalated Cell Kidney Knockout Mice Knowledge Life Liquid substance Lysine Maintenance Measurement Measures Mediating Medical Modeling Molecular Movement Na(+)-K(+)-Exchanging ATPase Nephrons Pathway interactions Phosphorylation Phosphotransferases Physiological Plasma Play Potassium Process Protein Isoforms Proteins Pump Regulation Role Signal Pathway Signal Transduction Stress Surface System Testing Urine Work base basolateral membrane cost extracellular falls hyperkalemia large-conductance calcium-activated potassium channels novel response sensor shear stress sodium-potassium-chloride cotransporter 1 protein ubiquitin ligase urinary voltage

项目摘要

The kidneys play a primary role in the maintenance of potassium homeostasis. The aldosterone sensitive distal nephron (ASDN) regulates potassium balance by matching the rate of urinary K+ excretion with changes in extracellular [K+]. Intercalated cells (ICs) play an important role in this process. Within these cells, apical large conductance BK channels open in response to shear stress to facilitate flow-induced K+ secretion (FIKS), a process activated by hyperkalemia. Though ICs mediate the transcellular movement of K+ from the peritubular interstitium into the tubule lumen, they are unique in that their basolateral K+ entry step is not carried out by the Na+/K+-ATPase. Instead, current evidence suggests that this process requires a bumetanide-sensitive Na+-K+-2Cl- cotransporter, NKCC1 (SLC12A2). NKCC1 is activated via direct phosphorylation, a process mediated by the WNK-SPAK/OSR1 pathway. Consistent with a role for this pathway in FIKS, we find that the kinase active forms of WNK1 and SPAK are stimulated in ICs during hyperkalemia, likely to activate basolateral NKCC1 and apical BK channels. This, however, contradicts the current paradigm, which contends that WNK kinases should be switched off when potassium levels are high in the blood. The overall goal of this application is to determine the importance of NKCC1 and the WNK-SPAK/OSR1 pathway in FIKS, and to test a novel mechanism that explains how these proteins are specifically activated in ICs of the ASDN during hyperkalemia. To accomplish this objective, we will use a variety experimental approaches, including whole animal studies, transport measurements in isolated perfused tubules, fluorescent cell sorting and isolation of ICs derived from whole kidney, and in vitro studies in cell culture models. The information gained from these studies will advance our knowledge of the molecular mechanisms underlying the ASDN’s response to potassium stress.

肾脏在维持钾稳态中起主要作用。醛固酮远端敏感