Ionic Homeostasis in Hypovolemia: Renal Mechanisms

低血容量时的离子稳态：肾脏机制

• 批准号: 6640510
• 负责人: Randi Beth Silver
• 金额: $ 34.49万
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640510
• 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+ 保持在严格限定的范围内对于维持生命至关重要。 K+ 稳态是身体的基本需求，但人们对 K^+ 的保存方式知之甚少。 K+保留是响应容量不足的重要稳态组成部分，可能发生在腹泻、利尿剂使用和充血性心力衰竭等情况下。 肾脏通过重新吸收更多的氯化钠来适应容量不足，但当氯化钠被重新吸收时，K+被保留的方式尚不清楚。 该项目的总体目标是阐明适应低血容量所涉及的肾脏 K+ 保存机制。 我认为钾重吸收发生在容量耗尽时，其机制涉及皮质集合管嵌入细胞中存在的 H+-K+-ATP 酶蛋白，这些蛋白质负责在容量耗尽的情况下保持钾+平衡。 此外，我认为皮质集合管中基底分泌插入细胞亚型中的顶端 Cl-/HCO-3 交换器是 Cl-重吸收伴随 Na+重吸收的机制。 具体目标 I 将检查体外研究中容量消耗对皮质集合管嵌入细胞中 H+-K+ ATP 酶和 CI/HCO-3 交换器活性的影响，以及肾皮质中 H+-K+-ATP 酶的丰度和定位匀浆并固定来自对照和容量耗尽的大鼠的肾脏。 体内研究将研究血管紧张素（肾素-血管紧张素-醛固酮系统的一部分，在容量耗尽时受到刺激）对 H+-K+-ATP 酶活性和 Cl/HCO-3 交换率的影响。 具体目标 II 将研究血管紧张素在体外急性调节嵌入细胞中 H+-K+-ATP 酶和 Cl-/HCO-3 交换器功能中的作用。 将研究与血管紧张素作用相关的两条信号转导途径，以确定血管紧张素如何对嵌入细胞运输发挥作用。 进行这些实验的总体前提是，如果我们了解身体通常保存 K+ 的生理基础，那么我们还将确定一个可能用于治疗 K+ 代谢紊乱的靶点。