Ionic Homeostasis in Hypovolemia: Renal Mechanisms

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。钾离子的体内平衡是人体的基本需要，但人们对钾离子守恒的方式知之甚少。钾离子保留是一个重要的稳态组成部分，以应对可能发生在腹泻、利尿剂使用和充血性心力衰竭等情况下的体积耗竭。肾脏通过重吸收更多的NaCI来适应体积损耗，但当NaCI被重吸收时，K+的保存方式尚不清楚。这个项目的总体目标是阐明肾K+保存机制参与适应低血容量。我提出，钾重吸收发生在体积损耗中，其机制涉及皮质集管嵌入细胞中的H+-K+- atp酶蛋白，这些蛋白负责在体积损耗条件下保持K+平衡。此外，笔者提出，在皮层收集管中分泌基底插层细胞亚型的顶端Cl-/HCO-3交换剂是Cl-重吸收伴随Na+重吸收的机制。我将在体外研究中检验体积损耗对皮质收集小管插层细胞中H+-K+- atp酶和CI/HCO-3交换物活性的影响，以及H+-K+- atp酶在对照大鼠和体积损耗大鼠肾皮质均浆和固定肾中的丰度和定位。体内研究将对血管紧张素（肾素-血管紧张素-醛固酮系统的一部分）对H+-K+- atp酶活性和Cl/HCO-3交换率的影响进行研究。特异性目的II将研究血管紧张素在体外插层细胞中急性调节H+- k +- atp酶和Cl-/HCO-3交换剂功能中的作用。为了确定血管紧张素如何在嵌入细胞运输中发挥作用，我们将研究与血管紧张素作用相关的两种信号转导途径。进行这些实验的总体前提是，如果我们了解了身体通常保存K+的生理基础，那么我们也将确定一个潜在的目标，可以用于治疗K+代谢障碍。

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.