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: 8141620
• 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/8141620
• 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; 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. PUBLIC HEALTH RELEVANCE: A large number of our veterans are admitted to the hospital each year with high blood pressure or abnormal acid base status. The distal nephron of the kidney plays a major role in vascular volume and blood pressure regulation and systemic acid base balance by regulating the transport of electrolytes and acid-base molecules in specialized cells and via specific transporters. We have identified two transport proteins in the kidney collecting duct that play important roles in the regulation of blood pressure and acid base homeostasis. We believe that the examination of the role of these transporters and their interaction with other transport proteins through the use of genetically engineered mouse models should provide novel insight into the pathogenesis of various diseases associated with increased blood pressure or abnormal acid base balance. Further, the information gathered can be eventually used to design therapeutic maneuvers aimed at correcting elevated blood pressure or excess loss of fluid or bicarbonate in the kidney.

描述(由申请人提供)： 肾小管中盐的排泄和吸收之间的平衡是血管容量、动态平衡和全身血压的主要决定因素。肾脏集合管通过特殊细胞中不同的转运体调节溶质、酸碱分子和液体的运输，在最终尿液的微调中发挥主要作用。收集管中氯的吸收或分泌构成了全身性盐平衡的主要组成部分。氯主要通过垂蛋白(SLC26A4)被非A细胞吸收，然而，对收集管中氯的分泌以及介导这一过程的分子(S)知之甚少。我们提供的证据表明，SLc26a9(PAT4)可以作为氯离子通道，定位于集合管主细胞的顶膜上。我们进一步报道，SLc26a9基因缺失的小鼠在缺水时排氯的能力降低。这些结果有力地表明，SLc26a9通过在集合管中发挥顶端氯通道的作用，在氯的排泄中发挥重要作用。此外，我们观察到SLc26a9小鼠的全身血压升高，高盐摄入量会加剧这种情况，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，在利尿剂导致盐向远端肾单位输送增加的反应中，旁腺素(SLC26A4)在收集管中的氯离子代偿性吸收中起主要作用。最后，继续我们现有的功绩回顾奖中提出的研究，我们报告了集合管特异性AE1缺失小鼠的产生。Ae1和Slc26a7(PAT2)都是表达在A细胞基侧膜上的Cl-/HCO3-交换分子，在外髓集合管的酸分泌和碳酸氢盐吸收中起重要作用。我们推测，SLc26a9(PAT4)通过调节集合管中肾氯的分泌，在血管容量动态平衡中发挥重要作用。因此，我们推测SLc26a9的下调或抑制可能在盐敏感型高血压的发病机制中起重要作用。我们推测侧链蛋白(SLC26A4)在利尿剂治疗后收集管对盐的代偿性吸收中起着重要作用。因此，我们假设，垂体素可以通过增加向远端肾单位输送的盐的吸收来增强对LOOP或DCT利尿剂(速尿或噻嗪衍生物)的抵抗或减弱其效果。最后，我们假设生理操作激活氯/HCO3-交换器PAT2或AE1可以减轻AE1或PAT2基因缺失小鼠远端肾小管酸中毒的严重程度。确定集合管氯转运体的作用将有助于阐明由盐吸收或排泄增强、酸碱失衡和血压失调引起的几种疾病的病理生理学机制。它们将进一步为利尿剂抵抗、盐敏感型高血压和酸碱稳态改变的患者提供新的治疗见解。 公共卫生相关性： 我们每年有大量退伍军人因高血压或酸碱状态异常而入院。肾脏远端肾单位通过调节特殊细胞中的电解质和酸碱分子的运输以及通过特定的转运体，在调节血管容量和血压以及全身酸碱平衡方面发挥重要作用。我们在肾脏集合管中发现了两种转运蛋白，它们在调节血压和酸碱平衡方面起着重要作用。我们相信，通过使用基因工程小鼠模型来检查这些转运蛋白的作用以及它们与其他转运蛋白的相互作用，应该会为与血压升高或异常酸碱平衡相关的各种疾病的发病机制提供新的见解。此外，收集到的信息最终可以用来设计旨在纠正血压升高或肾脏中液体或碳酸氢盐过量丢失的治疗方法。