Interplay of Renal Ca and Na Transport Pathways

肾钙和钠转运途径的相互作用

• 批准号: 7585652
• 负责人: JI-BIN PENG
• 金额: $ 26.22万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585652
• 关键词: Adult; Affect; Anabolism; Apical; Binding; Binding Sites; Biochemical; Blood Pressure; Calmodulin; Carrier Proteins; Cell Line; Cell membrane; Cells; Dietary Intervention; Disease; Distal; Distal convoluted renal tubule structure; Dose; Elderly; Employee Strikes; Epithelial; Equilibrium; Figs - dietary; Gatekeeping; Goals; Health; Heart failure; Hereditary Disease; Hypertension; Hypotension; Ions; Kidney; Knowledge; Link; Mediating; Molecular; Myocardial Infarction; Oocytes; Osteoporosis; Pathogenesis; Pathway interactions; Phosphotransferases; Physiological; Plasma; Play; Positioning Attribute; Protein Kinase; Regulation; Research; Research Personnel; Risk Factors; Role; Side; Stroke; Surface; Syndrome; System; Testing; Tetanus Helper Peptide; Work; Xenopus laevis; apical membrane; base; blood pressure regulation; expectation; experience; innovation; insight; mutant; novel strategies; pressure; prevent; programs; radiotracer; thiazide; trafficking; voltage

DESCRIPTION (provided by applicant): Hypertension occurs in nearly one out of every three US adults and is a major risk factor for stroke, heart attack, and heart failure. The molecular pathogenesis of hypertension is not well understood; however, recent findings from genetic disorders affecting blood pressure highlight the important roles of the thiazide- sensitive Na-CI cotransporter NCC and the WNK protein kinases in the distal tubule of the kidney in blood pressure regulation. Intriguingly, Na and Ca transport pathways in the distal tubule are inversely related; therefore, an increase in Ca transport in the distal tubule decreases the Na transport and in turn lowers the blood pressure. Hence, a detailed understanding of the interplay between the Na and Ca transport pathways is important in blood pressure regulation. As a gatekeeper for Ca reabsorption, TRPV5 is prominently localized in the apical membrane of the late segment of the distal convoluted tubule, where NCC and WNK4 are also expressed. WNK4 enhances TRPVS-mediated Ca transport in striking contrast to its inhibitory effect on NCC. Furthermore, the enhancing effect of WNK4 on TRPV5 is dose-dependently blocked by NCC. In addition, the enhancing effect of WNK4 on TRPV5 is abolished by chelating intracellular Ca. Based on these findings we hypothesize that WNK4 integrally regulates Na and Ca transport pathways by enhancing TRPV5 and suppressing NCC; the actions of WNK4 are also modulated by TRPV5 and NCC. We plan to test our hypothesis by pursuing three specific aims: 1) determine the mechanism by which WNK4 enhances TRPVS-mediated Ca transport; 2) determine the mechanism by which NCC modulates the action of WNK4; and 3) determine the role of Ca/calmodulin in modulating WNK4-mediated regulation. The studies will be carried out using molecular, biochemical and physiological approaches with both X. laevis oocytes and MDCK strain I cells. Stable MDCK I cell lines will be developed to assess the physiological significance of the regulation mechanisms. It is expected that new insights into the regulation of Ca and Na transport pathways through the interplay between the transport proteins and their common regulator WNK4 will be obtained at the completion of the project. With new knowledge acquired from the proposed studies, it is likely a new strategy via integral regulation of Na and Ca pathways in the distal tubule could be developed for blood pressure control.

描述（由申请人提供）：高血压发生在每三个美国成年人中的近一个，是中风，心脏病和心力衰竭的主要危险因素。高血压的分子发病机理尚不清楚。然而，影响血压的遗传疾病的最新发现突出了噻嗪敏感的Na-CI共转移蛋白NCC和WNK蛋白激酶在肾脏远端小管中的重要作用。有趣的是，远端小管中的Na和Ca传输途径成反比。因此，远端小管中Ca转运的增加会降低NA转运，进而降低血压。因此，对NA和CA传输途径之间相互作用的详细理解在血压调节中很重要。作为CA重吸收的守门人，TRPV5显着位于远端储备小管的晚期的顶部膜中，在其中也表达了NCC和WNK4。 WNK4与其对NCC的抑制作用形成鲜明对比，增强了TRPV介导的CA转运。此外，WNK4对TRPV5的增强作用被NCC依赖性地阻断。另外，通过螯合细胞内Ca来消除WNK4对TRPV5的增强作用。根据这些发现，我们假设WNK4通过增强TRPV5并抑制NCC来积分调节Na和Ca的传输途径。 WNK4的动作也由TRPV5和NCC调节。我们计划通过追求三个特定目标来检验我们的假设：1）确定WNK4增强TRPVS介导的CA运输的机制； 2）确定NCC调节WNK4作用的机制； 3）确定CA/钙调蛋白在调节WNK4介导的调节中的作用。研究将使用X. laevis卵母和MDCK菌株I细胞的分子，生化和生理方法进行。将开发稳定的MDCK I细胞系来评估调节机制的生理意义。可以预期，通过在项目完成时，将获得对CA和NA传输途径通过运输蛋白之间的相互作用及其共同调节剂WNK4之间相互作用的调节的新见解。通过从拟议的研究中获得的新知识，它可能是通过对远端小管中Na和Ca途径进行整体调节的新策略，可以开发出血压控制。