Ionic Homeostasis in Hypovolemia: Renal Mechanisms

低血容量时的离子稳态：肾脏机制

• 批准号: 6888944
• 负责人: Randi Beth Silver
• 金额: $ 28.56万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6888944
• 关键词: angiotensins; bicarbonates; electrolyte balance; hydrogen potassium exchanging ATPase; hypovolemia; laboratory rat; membrane transport proteins; potassium ion; renal tubular transport

DESCRIPTION (provided by applicant): Keeping serum K+ within narrowly defined limits is critical for the maintenance of life. K+ homeostasis is an essential need of the body, but the means by which K^+ is conserved are poorly understood. K+-sparing is an important homeostatic component in response to volume depletion as may occur in such conditions as diarrhea, diuretic use, and congestive heart failure. The kidney adapts to volume depletion by reabsorbing more NaCI but the means by which K+ is conserved when NaCI is reabsorbed is not understood. The overall objective of this project is to elucidate the renal K+ conserving mechanisms involved in the adaptation to hypovolemia. I propose that K reabsorption occurs in volume depletion via a mechanism involving H+-K+-ATPase proteins present in the intercalated cells of the cortical collecting duct and these proteins are responsible for preserving K+-balance under conditions of volume depletion. Further, I propose that the apical Cl-/HCO-3 exchanger in the base secreting intercalated cell subtype, in cortical collecting duct, is the mechanism by which Cl-reabsorption accompanies Na+ reabsorption. Specific Aim I will examine the effect of volume depletion in in vitro studies on the activities of the H+-K+ ATPase and CI/HCO-3 exchanger in intercalated cells of cortical collecting tubules, and H+-K+-ATPase abundance and localization in renal cortex homogenate and in fixed kidney from control and volume depleted rats. In vivo studies will be performed on the effects of angiotensin, part of the renin-angiotensin-aldosterone system, which is stimulated in voluime depletion, on H+-K+-ATPase activity and Cl/HCO-3 exchange rate. Specific Aim II will investigate the role of angiotensin in acutely regulating the function of H+-K+-ATPases and the Cl-/HCO-3 exchanger in intercalated cells in vitro. Two signal transduction pathways associated with the actions of angiotensin will be studied in order to determine how angiotensin exerts its effects on intercalated cell transport. The overall premise for conducting these experiments is that if we understand the physiological basis by which the body normaIly conserves K+, then we will also have identified a target that potentially can be exploited for therapy of disorders of K+ metabolism.

描述(由申请人提供)：将血清K+保持在严格定义的范围内对维持生命至关重要。K+动态平衡是人体的基本需要，但对K~+的保存方式却知之甚少。K+储备是应对容量耗竭的重要平衡成分，如腹泻、利尿剂使用和充血性心力衰竭。肾脏通过重新吸收更多的NaCI来适应容量耗竭，但当NaCI被重新吸收时，K+的保存方式尚不清楚。本项目的总体目标是阐明肾K+保存机制在适应低血容量中的作用。我认为在容量耗竭状态下，K的重吸收是通过存在于皮质集合管间隙细胞中的H+-K+-ATPase蛋白来实现的，这些蛋白负责在容量耗竭条件下维持K+-平衡。此外，笔者认为，在大脑皮层集合管的碱基分泌嵌插细胞亚型中，顶端的Cl-/HCO3-交换器是Cl-重吸收伴随Na+重吸收的机制。目的研究体外容量耗竭对大鼠肾皮质集合管间质细胞H+-K+-ATPase和CI/HCO-3交换活性的影响，以及肾皮质匀浆和固定肾中H+-K+-ATPase的丰度和定位。血管紧张素是肾素-血管紧张素-醛固酮系统的一部分，在体内研究血管紧张素对H+-K+-ATPase活性和氯/HCO-3交换率的影响。目的II研究血管紧张素在体外对细胞内H+-K+-ATPase和Cl-/HCO-3交换功能的调节作用。将研究两条与血管紧张素作用相关的信号转导途径，以确定血管紧张素如何在细胞间转运中发挥作用。进行这些实验的总体前提是，如果我们了解人体正常保存K+的生理基础，那么我们也将确定一个潜在的靶点，可以用于治疗K+代谢障碍。