Regulation of ANP Receptor Activity in Vascular Cells

血管细胞中 ANP 受体活性的调节

• 批准号: 7350182
• 负责人: David G Gardner
• 金额: $ 38.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7350182
• 关键词: Affect; Atrial Natriuretic Factor Receptors; Blood Pressure; Blood Vessels; Brain natriuretic peptide; Cardiovascular system; Cells; Dihydroxycholecalciferols; Down-Regulation; Duct (organ) structure; Endocrine; Extracellular Domain; Family; Funding; Gene Expression; Genes; Genetic Models; Genetic Transcription; Glucocorticoids; Guanylate Cyclase; Heart; Heart Atrium; Heart Hypertrophy; Homeostasis; Hormonal; In Vitro; Indium; Kidney; Knock-out; Ligand Binding; Ligands; Link; Mediating; Molecular; Mus; Natriuretic Peptides; Nuclear Receptors; Osmoregulation; Particulate; Peptides; Phosphotransferases; Play; Regulation; Renin-Angiotensin System; Role; Serum; Signal Transduction; Skeletal system; Smooth Muscle Myocytes; System; Transmembrane Domain; Up-Regulation; Vascular Smooth Muscle; Vitamin D; analog; atrial natriuretic factor receptor A; extracellular; familial hypertension; in vivo; receptor

The natriuretic peptides (NPs) collectively represent a family of hormonal peptides that play important roles in the control of renal, cardiovascular, endocrine and skeletal homeostasis. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BMP)signal predominantly through the type A natriuretic peptide receptor (NPR-A), a single transmembrane domain receptor which links a ligand-binding extracellular domain to a particulate guanylyl cyclase domain at the carboxy terminus of the molecule. Studies carried out during the previous funding period have demonstrated that the transcription of the NPR-A gene (nprl) is controlled by a extracellular tonicity as well as the nuclear receptor ligand 1,25 dihydroxyvitamin D(VD). NPR-A expression in the inner medullary collecting duct is osmotically regulated and a significant portion of this regulation is signaled by the serum and glucocorticoid inducible kinase (sgk) which is itself induced by increased extracellular tonicity. We have identified a candidate element in the sgkl promoterwhich we believe controls its osmoregulation, and inferentially the osmoregulation of this transcriptional cascade. We will attempt to elucidate the molecular details that govern this osmoregulatoryactivity. VD has been shown to possess a variety of palliative effects in the cardiovascular system including reduction in blood pressure and suppression of cardiac hypertrophy. We hypothesize that some portion of the palliative effects of VD in the heart and vasculature may be mediated through upregulation of NPR-A levels and activity. In the present proposalwe will use a combination of in vitro studies in VDR -/- cells, in vivo studies involving murine models of genetic hypertension and knockout of the VDR selectively in vascular smooth muscle and renal collecting duct cells in an attempt to confirm the mechanistic link betweenVD's cardio- and vasculoprotective activity and stimulation of NPR-A expression/activity. Collectively, this proposal should provide us with a detailed understanding of how the NPR-A gene is regulated and the role that this regulation plays in the control of cardiovascular homeostasis.

利尿钠肽 (NP) 共同代表了发挥重要作用的激素肽家族 控制肾脏、心血管、内分泌和骨骼稳态。心房钠尿肽 (ANP) B型利钠肽（BMP）信号主要通过A型利钠肽受体 (NPR-A)，一种单跨膜结构域受体，它将配体结合胞外结构域连接到 分子羧基末端的颗粒鸟苷酸环化酶结构域。期间进行的研究 之前的资助期已证明 NPR-A 基因 (nprl) 的转录是由 细胞外张力以及核受体配体 1,25 二羟基维生素 D (VD)。 内髓集合管中的 NPR-A 表达受到渗透压调节，并且很大一部分 这种调节是由血清和糖皮质激素诱导激酶 (sgk) 发出的，该激酶本身是由 细胞外张力增加。我们已经在 sgkl 启动子中确定了一个候选元件，我们将其 相信控制其渗透压调节，并推断该转录级联的渗透压调节。我们 将尝试阐明控制这种渗透调节活性的分子细节。 VD 已被证明对心血管系统具有多种姑息作用，包括减少 血压和抑制心脏肥大。我们假设某些部分 VD 对心脏和脉管系统的姑息作用可能是通过上调 NPR-A 水平来介导的 和活动。在本提案中，我们将结合使用 VDR -/- 细胞的体外研究和体内研究 涉及遗传性高血压小鼠模型和选择性敲除血管中 VDR 的研究 平滑肌和肾集合管细胞试图确认 VD 之间的机制联系 心脏和血管保护活性以及 NPR-A 表达/活性的刺激。总的来说，这 提案应该让我们详细了解 NPR-A 基因是如何调控的以及其作用 这种调节在心血管稳态的控制中发挥作用。