Role of Collecting Duct Chloride Transporters in Volume Regulation

收集管氯离子转运体在容量调节中的作用

• 批准号: 8598015
• 负责人: MANOOCHER SOLEIMANI
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598015
• 关键词: Acid-Base Equilibrium; Acids; Animals; Apical; Award; Bicarbonates; Blood Pressure; Blood Vessels; Carrier Proteins; Cells; Chloride Channels; Chloride Ion; Chlorides; Coupled; Data; Disease; Distal; Distal convoluted renal tubule structure; Distal renal tubular acidosis Type 1; Diuretics; Down-Regulation; Duct (organ) structure; Electrolytes; Equilibrium; Excretory function; Experimental Water Deprivation; Functional disorder; Furosemide; Generations; Genetic; Genetically Engineered Mouse; Homeostasis; Hospitals; Human; Hypertension; Injection of therapeutic agent; Intake; Intercalated Cell; Kidney; Knockout Mice; Light; Liquid substance; Mediating; Mus; Mutation; Nephrons; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Play; Process; Regulation; Relative (related person); Renal tubule structure; Reporting; Resistance; Role; Severities; Sodium Chloride; Therapeutic; Urine; Veterans; absorption; abstracting; apical membrane; base; basolateral membrane; blood pressure regulation; collecting tubule structure; design; information gathering; insight; meetings; mouse model; novel; novel therapeutics; response; salt intake; salt sensitive hypertension; solute; thiazide

DESCRIPTION (provided by applicant): The balance between salt excretion and absorption in the kidney tubules is a major determinant of vascular volume homeostasis and systemic blood pressure. The kidney collecting duct plays a major role in the fine tuning of the final urine by regulating the transport of solutes, acid base molecules and fluid via distinct transporters in specialized cells. The absorption or secretion of chloride in the collecting duct constitutes a major component of systemic salt homeostasis. Chloride is absorbed in non A-intercalated cells, predominantly via pendrin (Slc26a4), however, very little is known about chloride secretion in the collecting duct and the molecule(s) mediating this process. We provide evidence demonstrating that Slc26a9 (PAT4), which can function as a chloride channel, is localized on the apical membrane of principal cells in the collecting duct. We further report that mice with genetic deletion of Slc26a9 display reduced ability to excrete chloride when subjected to water deprivation. These results strongly suggest that Slc26a9 plays an important role in chloride excretion by functioning as an apical chloride channel in the collecting duct. Further, we observe that Slc26a9 mice display elevated systemic blood pressure, which is aggravated with high salt intake, a phenotype likely related to their reduced ability to secret chloride. We provide evidence demonstrating that pendrin (Slc26a4) plays a major role in compensatory chloride absorption in the collecting duct in response to increased delivery of salt to the distal nephron caused by diuretics. Lastly and continuing with the proposed studies in our existing Merit Review award, we report the generation of collecting duct specific AE1 null mice. Both AE1 and Slc26a7 (PAT2) are Cl-/HCO3- exchangers expressed on the basolateral membrane of A-intercalated cells and play an important role in acid secretion and bicarbonate absorption in the outer medullary collecting duct. We hypothesize that Slc26a9 (PAT4) plays a major role in vascular volume homeostasis by regulating renal chloride secretion in the collecting duct. As such, we hypothesize that the downregulation or inhibition of Slc26a9 may play an important role in the pathogenesis of salt sensitive hypertension. We hypothesize that pendrin (Slc26a4) plays an important role in compensatory salt absorption in the collecting duct in response to diuretic therapy. As such, we hypothesize that pendrin can confer resistance to or blunt the effect of loop or DCT diuretics (furosemide or thiazide derivatives) by increasing the absorption of salt delivered to the distal nephron. Lastly, we hypothesize that the activation of Cl-/HCO3- exchangers PAT2 or AE1 by physiologic maneuvers can mitigate the severity of distal renal tubular acidosis in AE1 or PAT2 null mice, respectively. Ascertaining the role of collecting duct chloride transporters should shed new light on the pathophysiology of several disorders resulting from enhanced salt absorption or excretion, acid base disorders and blood pressure dysregulation originating from distal nephron. They will further provide novel therapeutic insights in patients with diuretic resistance, salt sensitive hypertension and altered acid base homeostasis.

描述（由申请人提供）： 肾小管中盐排泄和吸收之间的平衡是血管容积稳态和全身血压的主要决定因素。肾集合管通过调节溶质、酸碱分子和液体经由特化细胞中的不同转运蛋白的转运，在最终尿液的微调中起主要作用。集合管中氯化物的吸收或分泌构成了全身盐稳态的主要组成部分。氯离子主要通过pendrin（Slc 26 a4）在非A-插入细胞中吸收，然而，对集合管中的氯离子分泌和介导该过程的分子知之甚少。我们提供的证据表明，Slc 26 a9（PAT 4），它可以作为一个氯离子通道，是本地化的集合管中的主细胞的顶膜。我们进一步报道，Slc 26 a9基因缺失的小鼠在缺水时表现出排泄氯离子的能力降低。这些结果有力地表明，Slc 26 a9通过在集合管中充当顶端氯离子通道而在氯离子排泄中起重要作用。此外，我们观察到Slc 26 a9小鼠表现出全身血压升高，这与高盐摄入量有关，这种表型可能与它们分泌氯化物的能力降低有关。我们提供的证据表明，pendrin（Slc 26 a4）起着重要的作用，在集合管中的补偿性氯离子吸收，以增加盐的输送到远端肾单位引起的利尿剂。最后，继续我们现有的Merit Review奖中提出的研究，我们报告了集合管特异性AE 1无效小鼠的产生。AE 1和Slc 26 a7（PAT 2）都是表达在A-插层细胞基底外侧膜上的Cl-/HCO 3-交换剂，在外髓集合管的酸分泌和碳酸氢盐吸收中发挥重要作用。我们推测Slc 26 a9（PAT 4）通过调节集合管中的肾氯化物分泌在血管容积稳态中起主要作用。因此，我们推测Slc 26 a9的下调或抑制可能在盐敏感性高血压的发病机制中起重要作用。我们假设pendrin（Slc 26 a4）在集合管对利尿剂治疗的代偿性盐吸收中起重要作用。因此，我们假设pendrin可以通过增加递送至远端肾单位的盐的吸收来赋予对袢或DCT利尿剂（呋塞米或噻嗪衍生物）的抗性或减弱其作用。最后，我们假设通过生理操作激活Cl-/HCO 3-交换器PAT 2或AE 1可以分别减轻AE 1或PAT 2缺失小鼠远端肾小管酸中毒的严重程度。确定收集管氯离子转运蛋白的作用，应阐明一些疾病的病理生理学引起的盐的吸收或排泄增强，酸碱平衡紊乱和血压失调，起源于远端肾单位。它们将进一步为利尿剂抵抗、盐敏感性高血压和酸碱平衡改变的患者提供新的治疗见解。