Role of vasopressin in regulating renal medullary gene expression

加压素在调节肾髓质基因表达中的作用

基本信息

批准号：
7903715
负责人：
HEDDWEN L BROOKS
金额：
$ 14.23万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7903715
关键词：
AVPR2 gene Address Animal Model Animals Apoptosis Biological Models Cells Congestive Heart Failure Data Defect Development Diabetes Mellitus Diabetic Nephropathy Disease Diuresis Diuretics Down-Regulation Duct (organ) structure Enzymes Excretory function GRP78 gene Gene Expression Genes Genetic Transcription Goals Heart failure Heat shock proteins Hypertension Individual Kidney Liquid substance Mediating Mus Osmolalities Pathogenesis Pathway interactions Patients Permeability Play Process Renal Tissue Renal function Research Personnel Role Signal Pathway Signal Transduction Signaling Pathway Gene Sodium Sodium Chloride Solid Stress Suspension substance Suspensions Testosterone Transcriptional Regulation Translations Up-Regulation V2 Receptors Vasopressin Receptor Vasopressins Water aquaporin-2 diabetic endoplasmic reticulum stress epithelial Na+ channel in vivo kidney cell kidney medulla novel peptide hormone preconditioning programs receptor solute steroid hormone stress protein

项目摘要

DESCRIPTION (provided by applicant): Diabetes and congestive heart failure are diseases that have been associated with defects in the handling of salt and water by the kidney. Common in individuals with these disorders are elevated circulating levels of vasopressin, the peptide hormone that regulates renal water excretion. Circulating vasopressin plays a critical role in extra-cellular fluid expansion and development of hypertension, thus contributes to the pathogenesis of the disease. Vasopressin has clear long-term actions in the kidney, associated with vasopressin receptor activated processes and transcriptional regulation. Circulating vasopressin also increases the concentrating capacity of the renal medulla by activating the counter current mechanism. The result is an increase in medullary osmotic stress that can directly activate renal cell signaling pathways and gene transcription. Thus specific effects of vasopressin on gene expression are not delineated from secondary alterations associated with this change in medullary osmolality. Preliminary data, from in vivo studies in mice, identifies a role for vasopressin in activating endoplasmic reticulum stress (ER stress) in collecting duct cells. ER stress may be the key to how collecting duct cells survive large increases in medullary osmotic stress during anti-diuresis. Thus we will determine if vasopressin plays a preconditioning role in the medulla to protect collecting duct cells from apoptosis while continuing to upregulate aquaporin-2 expression and increase collecting duct water permeability. We have also identified a novel vasopressin- signaling pathway that decreases the expression of steroid hormone inactivating enzymes in the collecting duct and propose that this vasopressin-mediated pathway may indirectly enhance ENaC expression. Our studies will utilize three complementary model systems, cells, tubule suspensions and animal models to address our central hypothesis that vasopressin promotes AQP2- and ENaC-dependent pathways through direct (V2R) and indirect (osmotic stress) mechanisms. Specific Aims are: 1) To determine if increases in local solute concentrations activate ER stress proteins and protect collecting duct cells from further osmotic stress 2) To determine if vasopressin directly mediates the up-regulation of ER stress proteins via a V2 receptor pathway 3) To determine if vasopressin directly mediates the down-regulation of steroid hormone enzymes via a V2 receptor pathway.

描述（由申请人提供）：糖尿病和充血性心力衰竭是与肾脏处理盐和水的缺陷有关的疾病。患有这些疾病的个体常见的是加压素循环水平升高，加压素是调节肾水排泄的肽激素。循环加压素在细胞外液扩张和高血压的发展中起着关键作用，从而促进了该疾病的发病机制。加压素在肾脏中具有明显的长期作用，与加压素受体激活过程和转录调节有关。循环加压素还通过激活逆流机制来增加肾髓质的浓缩能力。其结果是髓质渗透压增加，可以直接激活肾细胞信号传导途径和基因转录。因此，加压素对基因表达的具体作用并未从与髓质渗透压变化相关的继发性改变中描述出来。来自小鼠体内研究的初步数据确定了加压素在激活集合管细胞内质网应激（ER 应激）中的作用。内质网应激可能是集合管细胞如何在抗利尿期间髓质渗透应激大幅增加的情况下生存的关键。因此，我们将确定加压素是否在髓质中发挥预处理作用，以保护集合管细胞免于凋亡，同时继续上调 aquaporin-2 表达并增加集合管水渗透性。我们还发现了一种新的加压素信号通路，可降低集合管中类固醇激素失活酶的表达，并提出这种加压素介导的通路可能会间接增强 ENaC 的表达。我们的研究将利用三个互补的模型系统、细胞、肾小管悬浮液和动物模型来解决我们的中心假设，即加压素通过直接 (V2R) 和间接（渗透应激）机制促进 AQP2 和 ENaC 依赖性途径。具体目标是： 1) 确定局部溶质浓度的增加是否会激活 ER 应激蛋白并保护集合管细胞免受进一步的渗透应激 2) 确定加压素是否通过 V2 受体途径直接介导 ER 应激蛋白的上调 3)确定加压素是否通过 V2 受体途径直接介导类固醇激素酶的下调。