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Regulation of intercalated cell function by the mineralocorticoid receptor

盐皮质激素受体对闰细胞功能的调节

基本信息

批准号：
10319975
负责人：
SUSAN MARIE WALL
金额：
$ 39万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319975
关键词：
Ablation Acids Actins Address Aldosterone Angiotensin II Animals Apical Attenuated Bicarbonates Binding Blood Pressure Cardiovascular Diseases Cell Nucleus Cell membrane Cell physiology Cells Cytoskeletal Modeling Cytoskeletal Proteins Data Diet Duct (organ) structure Epidemic Equilibrium Family Gene Expression Genes Genetic Transcription Glucocorticoids Guanosine Triphosphate Phosphohydrolases Human Hypertension Hypokalemia Immunohistochemistry In Vitro Industrialization Intake Intercalated Cell Ion Transport Kidney Kidney Diseases Knockout Mice Ligand Binding Mediating Microscopy Mineralocorticoid Receptor Minority Modeling Molecular Mus Protein Dephosphorylation Publishing Receptor Activation Receptor Gene Receptor Signaling Regulation Renal tubule structure Rodent Model Role Signal Transduction Sodium Chloride Testing Time Work absorption apical membrane base blood pressure elevation blood pressure regulation cardiovascular risk factor cell type cytochemistry epithelial Na+ channel extracellular in vivo inhibitor prevent public health relevance receptor response rho rho GTP-Binding Proteins salt balance salt sensitive hypertension uptake

项目摘要

7. PROJECT SUMMARY AND RELEVANCE: While Na+ intake exacerbates hypertension, blood pressure also rises with increased Cl- intake, independently of Na+, making Cl- intake and renal Cl- absorption critical in blood pressure regulation. Aldosterone administration in vivo increases NaCl uptake by the cortical collecting duct (CCD) primarily through principal cell-mediated Na+ absorption and intercalated cell-mediated Cl- absorption, which occurs in exchange for HCO3-, largely through the Cl-/HCO3- exchanger, pendrin. How Cl- contributes to hypertension and, in particular, how aldosterone stimulates IC Cl-/HCO3- exchange is poorly understood. Aldosterone’s signaling mechanism in principal cells is well established. 11 HSD2 metabolizes cellular glucocorticoids enabling aldosterone binding to the MR (Nr3c2), thereby stimulating ENaC. However, published and preliminary data show that the signaling mechanism(s) of aldosterone and the MR are very different in ICs. First, 11 HSD2 is not expressed in ICs. Second, MR inhibitors reduce IC transporter abundance even in the known absence of aldosterone. Third, published and preliminary data show angiotensin II and a high NaCl diet can activate the MR independently of aldosterone, likely through a mechanism involving Rac1, a GTPase in the Rho family, that regulates cytoskeletal reorganization and gene expression. We observed that Rac1 gene ablation or Rac1 inhibition reduces pendrin abundance in angiotensin II-treated mice. We observed that increased NaCl intake reduces Cl- absorption and Cl- transporter abundance in CCDs from untreated mice, but increases the apical plasma membrane abundance of intercalated cell Cl- transporters in angiotensin II-treated mice. We therefore hypothesize that IC MR activation occurs through or independently of aldosterone. We also hypothesize that angiotensin II-induced IC MR activation occurs through Rac1 and the MR, which act a molecular switch, by which the effect of NaCl intake IC Cl- transporter abundance and function (IC Cl-/HCO3- exchange) changes from inhibitory to stimulatory. To study IC transporter regulation by the IC MR, we developed mice lacking the mineralocorticoid receptor and Rac1 in intercalated cells (IC MR KO and IC Rac1 KO mice). Determining how aldosterone and angiotensin II target intercalated cells may provide additional targets for hypertension. Proposal Aims are to determine: 1) if the mineralocorticoid receptor modulates intercalated cell transporter abundance and function, blood pressure and salt balance, 2) if the mineralocorticoid receptor stimulates intercalated cell function independently of aldosterone or aldosterone binding and 3) If angiotensin II acts through the MR and Rac1 to modulate the effect of NaCl intake on IC transporter abundance and function. We will examine the effect of K+, aldosterone, angiotensin II and the MR on intercalated cell transporter abundance and function in vivo and in vitro with quantitative real time PCR, immunohistochemistry, immunogold cytochemistry, renal tubules perfused in vitro and in whole animal studies.

7. 项目概况及相关性：

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pendrin abundance, subcellular distribution, and function are unaffected by either αENaC gene ablation or by increasing ENaC channel activity.

DOI：
10.1007/s00424-023-02797-w
发表时间：
2023-05
期刊：
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
影响因子：
4.5
作者：
Loffing, Johannes;Pech, Vladimir;Loffing-Cueni, Dominique;Abood, Delaney C.;Kim, Young Hee;Chen, Chao;Pham, Truyen D.;Verlander, Jill W.;Wall, Susan M.
通讯作者：
Wall, Susan M.

Thrombocytopenia Induced by Polysulfone Dialysis Membranes.