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）： 盐小管中盐分排泄和吸收之间的平衡是血管体积稳态和全身血压的主要决定因素。肾脏收集管道通过在专用细胞中通过不同的转运蛋白调节溶质，酸碱分子和液体的运输，在最终尿液的微调中起主要作用。收集管道中氯化物的吸收或分泌构成了全身性盐稳态的主要组成部分。氯化物被主要通过pendrin（SLC26A4）吸收在非A间接细胞中，但是，对于收集管中的氯化物分泌知之甚少，分子和介导该过程的分子。我们提供的证据表明，可以用作氯化物通道的SLC26A9（PAT4）位于收集管中主要细胞的顶膜上。我们进一步报告，遗传缺失的SLC26A9的小鼠在受到水剥夺时表现出降低的排泄氯化物的能力。这些结果强烈表明，SLC26A9在收集管中充当顶端氯化物通道在氯化物排泄中起重要作用。此外，我们观察到SLC26A9小鼠表现出升高的全身性血压，该血压被高盐摄入加剧，这是一种可能与降低氯化物的能力有关的表型。我们提供的证据表明，pendrin（SLC26A4）在收集导管中的补偿性氯化物吸收中起着重要作用，这是由于盐的递送到由利尿剂引起的远端肾脏的递送而产生的。最后，在我们现有的功绩审查奖中的拟议研究中继续，我们报告了收集特定AE1 NULL小鼠的生成。 AE1和SLC26A7（PAT2）均为在A间接细胞的基底外侧膜上表达的Cl-/HCO3-交换器，并且在髓样收集管中的酸分泌和碳酸氢盐吸收中起重要作用。我们假设SLC26A9（PAT4）通过调节收集管中的肾氯化物分泌在血管体积稳态中起重要作用。因此，我们假设SLC26A9的下调或抑制可能在盐敏感高血压的发病机理中起重要作用。我们假设Pendrin（SLC26A4）在响应利尿治疗的收集导管中的补偿性盐吸收中起重要作用。因此，我们假设pendrin可以通过增加盐的吸收到远端肾单位的盐的吸收来赋予或钝化循环或dct利尿剂（速尿或噻嗪类衍生物）的影响。最后，我们假设通过生理操作的Cl-/HCO3-交换器PAT2或AE1的激活可以分别缓解AE1或PAT2 NULL小鼠中远端肾小管酸中毒远端肾小管酸中毒的严重程度。确定收集导管氯化物转运蛋白的作用应为盐吸收或排泄增加，酸碱疾病和血压失调而产生的几种疾病的病理生物生物生物生物生物生物生物学作用，并发出新的启示。他们将进一步提供利尿性耐药性，盐敏感性高血压和酸化酸基稳态的患者的新型治疗见解。