Regulation of Pendrin by Angiotensin II

血管紧张素 II 对 Pendrin 的调节

• 批准号: 8135539
• 负责人: SUSAN MARIE WALL
• 金额: $ 38.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135539
• 关键词: Aldosterone; Alkalosis; Angiotensin II; Animals; Apical; Attenuated; Bicarbonates; Blood Pressure; Blood Vessels; Carbon Dioxide; Cell membrane; Cells; Chloride Ion; Chlorides; Colon; Deoxycorticosterone; Diet; Distal; Duct (organ) structure; Epithelial; Equilibrium; Genes; Genetic; Hypertension; Immunoblotting; Immunohistochemistry; In Vitro; Intake; Intercalated Cell; Kidney; Knockout Mice; Laboratories; Light; Measurement; Mediating; Metabolic; Microscopic; Mus; Mutant Strains Mice; Process; Production; Proteins; Proton-Translocating ATPases; Regulation; Renal tubule structure; Rodent Model; Sodium; Sodium Channel; Sodium Chloride; Syndrome; Thyroid Gland; Time; Tissues; absorption; analog; carbonate dehydratase; cytochemistry; driving force; epithelial Na+ channel; in vivo; kidney cell; mouse model; protein expression; protein transport; receptor; response; uptake

DESCRIPTION (provided by applicant): Type B intercalated cells secrete HCO3- and absorb Cl- across the apical plasma membrane through the action of the Cl-/HCO3- exchanger, pendrin. Pendrin-mediated Cl-/HCO3- exchange reduces arterial pH and HCO3- concentration, thereby attenuating a metabolic alkalosis. Pendrin-mediated Cl- absorption also contributes to the vascular volume expansion observed in rodent models of NaCl-sensitive hypertension, such as following a high NaCl diet and aldosterone analogues (deoxycorticosterone pivalate, DOCP). We have observed that the hypertension expected with DOCP administration and a high NaCl diet is not observed in mice with genetic disruption of the gene encoding pendrin (Slc26a4). The absence of aldosterone-induced hypertension in Slc26a4 null mice occurs most likely not only from the absence of pendrin-mediated Cl- uptake but also from the reduced epithelial Na+ channel (ENaC) expression observed in the kidneys of these mutant mice. However, pendrin and ENaC are regulated through both aldosterone-dependent and -independent mechanisms. Our laboratory and others have shown that angiotensin II stimulates Na+ and Cl- absorption in the cortical collecting duct (CCD) when perfused in vitro through synergy between pendrin and ENaC. How angiotensin II stimulates pendrin and ENaC expression and function and how pendrin and ENaC interact to promote NaCl absorption is the subject of the present proposal. The aims of this proposal are the following: 1) to determine the mechanism whereby angiotensin II stimulates pendrin-mediated Cl-/HCO3- exchange in vitro and to determine how ENaC and pendrin interact following angiotensin II to increase NaCl absorption, 2) to determine the mechanism of the long-term regulation of pendrin by angiotensin II in vivo and how pendrin modulates ENaC expression in vivo and 3) to determine the mechanism for the interdependency of pendrin and ENaC expression. To accomplish these objectives wild type and genetically modified mice, such as Slc26a4 (-/-), total and cell-specific AT1a (-/-), tissue-specific ENaC (-/-) and mouse models of Liddle's Syndrome, will be studied using quantitative real time PCR, light microscopic immunohistochemistry, immunogold cytochemistry and immunoblots. Transport will be studied in mouse renal tubules perfused in vitro and in cultured mouse principal cells. Whole animal studies will be employed further in balance studies and measurements of blood pressure and GFR.7. Project Narrative: Our laboratory has observed that a protein called pendrin mediates absorption of chloride by the kidney, which increases blood pressure. In addition, pendrin also regulates absorption of sodium by the kidney by changing the amount of a protein that transports sodium within the kidney (i.e. the epithelial sodium channel, ENaC). This proposal will explore how pendrin controls absorption of sodium and chloride by the kidney.

描述（由申请方提供）：B型插入细胞分泌HCO 3-，并通过Cl-/HCO 3-交换剂pendrin的作用吸收Cl-穿过顶端质膜。Pendrin介导的Cl-/HCO 3-交换降低动脉pH和HCO 3-浓度，从而减弱代谢性水肿。Pendrin介导的Cl-吸收也有助于在NaCl敏感性高血压的啮齿动物模型中观察到的血管体积扩张，例如在高NaCl饮食和醛固酮类似物（新戊酸脱氧皮质酮，DOCP）之后。我们已经观察到，在具有pendrin编码基因（Slc 26 a4）的遗传破坏的小鼠中没有观察到DOCP施用和高NaCl饮食所预期的高血压。在Slc 26 a4缺失小鼠中不存在醛固酮诱导的高血压最可能不仅是由于不存在pendrin介导的Cl-摄取，而且还由于在这些突变小鼠的肾脏中观察到的上皮Na+通道（ENaC）表达减少。然而，pendrin和ENaC通过醛固酮依赖性和非依赖性机制调节。我们的实验室和其他人已经表明，血管紧张素II刺激Na+和Cl-吸收皮质集合管（CCD）在体外灌注时，通过pendrin和ENaC之间的协同作用。血管紧张素II如何刺激pendrin和ENaC的表达和功能以及pendrin和ENaC如何相互作用以促进NaCl吸收是本提案的主题。这项建议的目的如下：1）确定血管紧张素II在体外刺激pendrin介导的Cl-/HCO 3-交换的机制，并确定ENaC和pendrin在血管紧张素II后如何相互作用以增加NaCl吸收，2）确定血管紧张素II在体内长期调节pendrin的机制以及pendrin如何在体内调节ENaC表达，以及3）以确定pendrin和ENaC表达相互依赖的机制。为了实现这些目标，将使用定量真实的时间PCR、光镜免疫组织化学、免疫金细胞化学和免疫印迹研究野生型和遗传修饰小鼠，例如Slc 26 a4（-/-）、总和细胞特异性AT 1a（-/-）、组织特异性ENaC（-/-）和Liddle综合征小鼠模型。将在体外灌注的小鼠肾小管和培养的小鼠主细胞中研究转运。将在平衡研究和血压和GFR测量中进一步采用整体动物研究。7. 项目叙述：我们的实验室已经观察到一种叫做pendrin的蛋白质介导了肾脏对氯化物的吸收，从而增加了血压。此外，pendrin还通过改变在肾脏内转运钠的蛋白质（即上皮钠通道，ENaC）的量来调节肾脏对钠的吸收。该提案将探讨pendrin如何控制肾脏对钠和氯的吸收。

项目成果

Impact of K(+) homeostasis on net acid secretion in rat terminal inner medullary collecting duct: role of the Na,K-ATPase.

K( )稳态对大鼠终末内髓集合管净酸分泌的影响：Na,K-ATP酶的作用。

• DOI: 10.1053/ajkd.2000.19115
• 发表时间: 2000
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation
• 作者: Wall,SM

Angiotensin II activates H+-ATPase in type A intercalated cells.

血管紧张素 II 激活 A 型闰细胞中的 H -ATP 酶。

• DOI: 10.1681/asn.2007030277
• 发表时间: 2008
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Pech,Vladimir;Zheng,Wencui;Pham,TruyenD;Verlander,JillW;Wall,SusanM
• 通讯作者: Wall,SusanM

In rat inner medullary collecting duct, NH uptake by the Na,K-ATPase is increased during hypokalemia.

在大鼠内髓集合管中，低钾血症期间 Na,K-ATP 酶对 NH 的吸收增加。

• DOI: 10.1152/ajprenal.0141.2001
• 发表时间: 2002
• 期刊: American journal of physiology. Renal physiology
• 作者: Wall,SusanM;Fischer,MichaelP;Kim,Gheun-Ho;Nguyen,Bich-May;Hassell,KathrynA
• 通讯作者: Hassell,KathrynA

NaCl restriction upregulates renal Slc26a4 through subcellular redistribution: role in Cl- conservation.

氯化钠限制通过亚细胞重新分布上调肾脏 Slc26a4：在 Cl- 保存中的作用。

• DOI: 10.1161/01.hyp.0000145863.96091.89
• 发表时间: 2004
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Wall,SusanM;Kim,YoungHee;Stanley,Lorraine;Glapion,DawnM;Everett,LorraineA;Green,EricD;Verlander,JillW
• 通讯作者: Verlander,JillW

Pendrin and sodium channels: relevance to hypertension.

• 发表时间: 2010-11
• 期刊: Journal of nephrology
• 影响因子: 3.4
• 作者: S. Wall;Vladimir Pech