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: 8392102
• 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/8392102
• 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.

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稳态和全身血压的主要决定因素。肾集合管通过特殊细胞中的不同转运蛋白调节溶质、酸碱分子和液体的转运，在最终尿液的微调中发挥着重要作用。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。氯离子在非 A 嵌入细胞中主要通过 pendrin (Slc26a4) 被吸收，然而，对于集合管中的氯离子分泌以及介导该过程的分子知之甚少。我们提供的证据表明，Slc26a9 (PAT4) 可充当氯离子通道，位于集合管主细胞的顶膜上。我们进一步报告，Slc26a9 基因缺失的小鼠在缺水时排泄氯化物的能力降低。这些结果强烈表明，Slc26a9 通过充当集合管中的顶端氯离子通道，在氯离子排泄中发挥重要作用。此外，我们观察到 Slc26a9 小鼠表现出全身血压升高，高盐摄入会加剧这种情况，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，pendrin (Slc26a4) 在集合管中代偿性氯吸收中发挥着重要作用，以响应利尿剂引起的向远端肾单位的盐输送增加。最后，继续我们现有的优异奖评审中提出的研究，我们报告了集合管特异性 AE1 缺失小鼠的产生。 AE1 和 Slc26a7 (PAT2) 都是在 A 嵌入细胞的基底外侧膜上表达的 Cl-/HCO3- 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。我们假设 Slc26a9 (PAT4) 通过调节集合管中肾氯的分泌在血管容量稳态中发挥重要作用。因此，我们假设 Slc26a9 的下调或抑制可能在盐敏感性高血压的发病机制中发挥重要作用。我们假设 pendrin (Slc26a4) 在响应利尿治疗的集合管中代偿性盐吸收中发挥重要作用。因此，我们假设 pendrin 可以通过增加输送到远端肾单位的盐的吸收来赋予对袢利尿剂或 DCT 利尿剂（呋塞米或噻嗪类衍生物）的抵抗力或减弱其作用。最后，我们假设通过生理操作激活 Cl-/HCO3-交换器 PAT2 或 AE1 可以分别减轻 AE1 或 PAT2 缺失小鼠远端肾小管酸中毒的严重程度。确定集合管氯化物转运蛋白的作用应该为一些由远端肾单位引起的盐吸收或排泄增强、酸碱紊乱和血压失调引起的疾病的病理生理学提供新的线索。他们将进一步为利尿抵抗、盐敏感性高血压和酸碱稳态改变的患者提供新的治疗见解。