The role of collecting duct chloride transporters in salt absorption and blood pressure homeostasis

集合管氯离子转运蛋白在盐吸收和血压稳态中的作用

• 批准号: 9898225
• 负责人: MANOOCHER SOLEIMANI
• 金额: --
• 依托单位: ALBUQUERQUE VA MEDICAL CENTER
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898225
• 关键词: Ablation; Aldosterone; Amiloride; Animals; Anions; Bicarbonates; Blood Pressure; Blood Vessels; Blood Volume; Carrier Proteins; Chlorides; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Congestive Heart Failure; DOCA; Development; Disease; Distal; Diuresis; Diuretics; Duct (organ) structure; Enterobacteria phage P1 Cre recombinase; Equilibrium; Excess Dietary Salt; Excretory function; Exhibits; Family; Financial compensation; Fluid overload; Fluorescence; Furosemide; Genes; Genetically Engineered Mouse; Goals; Health; Homeostasis; Hospitals; Hydrochlorothiazide; Hypertension; Intercalated Cell; Ions; Kidney; Knockout Mice; Laboratories; Length; Liquid substance; Measurement; Mediating; Metabolic; Molecular; Monitor; Mus; Nephrons; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Radioactive; Regulation; Research; Research Personnel; Role; SLC12A3 gene; Sodium; Sodium Chloride; Systemic blood pressure; Telemetry; Therapeutic; Veterans; Work; absorption; apical membrane; blood pressure regulation; collecting tubule structure; design; dietary salt; epithelial Na+ channel; inhibitor/antagonist; innovation; insight; member; mutant; mutant mouse model; novel; patch clamp; response; salt intake; thiazide; wasting

The paradigm has long held that the epithelial Na channel ENaC, in conjunction with paracellular Cl- absorption, is the major path for salt absorption in the collecting duct whereas NCC is the main salt absorbing transporter in the DCT. Studies over the last decade have identified several new players in transcellular chloride and/or sodium reabsorption in the collecting duct (CD), including the Cl-/HCO3- exchanger Slc26a4 (pendrin), the Na+- dependent Cl-/HCO3- exchanger Slc4a8 (NDCBE), and the chloride transporter/channel Slc26a11 (KBAT). Unlike mice with single deletion of NCC or pendrin, simultaneous deletion of pendrin and NCC causes sharp increases in salt excretion, pointing to cross compensation between NCC and pendrin and their crucial role in salt absorption. No transcellular chloride-absorbing pathway has been identified in medullary collecting duct. New studies from our laboratory demonstrate that Slc26a11 (KBAT) is expressed on the apical membrane of A- intercalated cells in CCD, OMCD and iIMCD and plays an important role in salt absorption. The schematic diagrams in Figs. 2, 6 and 7 depict the interaction of KBAT and pendrin with other ion transporters in the CCD. Preliminary results: KBAT expression is enhanced in response to furosemide treatment, NCC or pendrin deletion, and salt loading, raising the possibility that KBAT plays an important role in salt absorption in the setting of enhanced delivery of salt to the collecting duct. We have generated mice with kidney specific [(or global)] ablation of KBAT, which show significant salt wasting in response to the loop diuretics or following increased dietary salt intake. Hypothesis: We hypothesize that KBAT plays an important role in salt absorption in the entire collecting duct, cross compensates for NCC or pendrin inactivation and/or inhibition and mitigates the salt loss in response to enhanced salt delivery to the collecting duct. As a result, we predict that KBAT inactivation will result in excess salt wasting consequent to diuretic therapy, in the setting of NCC or pendrin inhibition/inactivation, and in response to salt loading, the latter reflecting a unique role for this transporter in salt absorption in salt replete states [and in salt/DOCA hypertension]. Lastly, we hypothesize that KBAT and pendrin work in tandem with ENaC and/or NDCBE [(the global KO of the latter has been generated in our lab)] to reabsorb salt in CD. Innovation: The proposed research will elucidate the role of KBAT and pendrin as major players in salt reabsorption in distal nephron and as novel targets for diuretic therapy. Approach: A combination of genetically engineered mouse models, metabolic balance studies, tubule microperfusion, systemic blood pressure measurement by telemetry and molecular studies will be employed to ascertain the role of KBAT and pendrin in salt reabsorption and identify their sodium absorbing partners in the collecting duct. Insight into the role of KBAT and pendrin will significantly enhance our understanding of the role of these transporters in salt reabsorption and blood pressure homeostasis. The proposed studies will further lay the ground for development of inhibitors of KBAT and pendrin as novel diuretics in fluid overloaded states.

范式长期以来一直认为上皮Na通道ENAC与细胞细胞cl-吸收相结合， 是收集管中盐吸收的主要途径，而NCC是吸收主要盐的转运蛋白 DCT。在过去的十年中，研究确定了跨细胞氯化物和/或钠的几个新参与者 收集管（CD）中的重吸收，包括Cl-/hco3-交换器SLC26A4（Pendrin），Na+ - 依赖性Cl-/HCO3-交换器SLC4A8（NDCBE）和氯化物转运蛋白/通道SLC26A11（KBAT）。 与单一删除NCC或Pendrin的小鼠不同，Pendrin和NCC同时删除急剧 盐分排泄的增加，指出NCC和Pendrin之间的交叉补偿及其在 吸收盐。在髓质收集导管中尚未确定跨氯化物吸收途径。 我们实验室的新研究表明，SLC26A11（KBAT）在A-的顶膜上表达 CCD，OMCD和IIMCD中的插入细胞在吸收盐中起重要作用。示意图 图2中的图。 2、6和7描述了CCD中Kbat和Pendrin与其他离子转运蛋白的相互作用。 初步结果：响应速尿治疗，NCC或Pendrin，KBAT表达得到增强 缺失和盐负荷增加了KBAT在盐吸收中起重要作用的可能性 盐向收集管道的递送增强。我们已经产生了特定于肾脏的小鼠[（或全球）] KBAT的消融，该KBAT显示出响应循环利尿剂或随后增加的盐分浪费 饮食盐的摄入量。假设：我们假设KBAT在整个盐吸收中起重要作用 收集管道，交叉补偿NCC或Pendrin灭活和/或抑制作用，并减轻盐分损失 响应增强的盐分输送到收集管道。结果，我们预测KBAT灭活将 在NCC或Pendrin的情况下，导致了利尿治疗导致过量的盐浪费 抑制/灭活，并响应盐负荷，后者反映了该转运蛋白在盐中的独特作用 盐饱和态的吸收[以及盐/DOCA高血压]。最后，我们假设KBAT和Pendrin 与ENAC和/或NDCBE协同工作[（后者的全球KO已在我们的实验室中生成）] CD中的盐。创新：拟议的研究将阐明KBAT和Pendrin作为主要参与者的作用 远端的盐分吸收盐，作为利尿治疗的新靶标。方法：结合 基因工程的小鼠模型，代谢平衡研究，小管微灌注，全身血液 通过遥测和分子研究的压力测量将用于确定KBAT和 盐在盐中吸收的pendrin，并鉴定其吸收钠的伴侣在收集管道中。深入了解 KBAT和PENDRIN的作用将显着增强我们对这些转运蛋白在盐中的作用的理解 重吸收和血压稳态。拟议的研究将进一步为发展奠定基础 KBAT和PENDRIN的抑制剂是流体超载状态下的新利尿剂。