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

• 批准号: 7765836
• 负责人: HEDDWEN L BROOKS
• 金额: $ 0.15万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765836
• 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

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相关的疾病。这些疾病患者的常见症状是血管加压素循环水平升高，血管加压素是一种调节肾水排泄的肽类激素。循环加压素在细胞外液扩张和高血压的发生发展中起着重要作用，从而参与了高血压的发病机制。加压素在肾脏中具有明确的长期作用，与加压素受体激活过程和转录调控相关。循环加压素也通过激活逆流机制增加肾髓质的浓缩能力。结果是髓质渗透压增加，可直接激活肾细胞信号通路和基因转录。因此，加压素对基因表达的特异性作用不能从与髓质渗透压变化相关的继发性改变中得到描述。来自小鼠体内研究的初步数据确定了加压素在集合管细胞中激活内质网应激（ER应激）的作用。内质网压力可能是关键集合管细胞如何生存的髓质渗透压在抗利尿剂的大幅增加。因此，我们将确定加压素是否在髓质中起预处理作用，以保护集合管细胞免于凋亡，同时继续上调水通道蛋白-2表达并增加集合管水渗透性。我们还确定了一种新的加压素信号通路，减少类固醇激素失活酶在集合管的表达，并提出，这种加压素介导的途径可能间接增强ENaC的表达。我们的研究将利用三个互补的模型系统，细胞，小管悬浮液和动物模型，以解决我们的中心假设，加压素促进AQP 2和ENaC依赖的途径，通过直接（V2 R）和间接（渗透压）机制。具体目标是：1）确定局部溶质浓度的增加是否激活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。