gamma-MSH and Sodium Metabolism

γ-MSH 和钠代谢

• 批准号: 7035374
• 负责人: MICHAEL H HUMPHREYS
• 金额: $ 33.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035374
• 关键词: antihypertensive agents; brain mapping; clinical research; denervation; dietary sodium; dopamine; essential hypertension; genetic strain; genetic susceptibility; hormone receptor; hormone regulation /control mechanism; human subject; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; melanocyte stimulating hormone; neuroregulation; nutrition related tag; pathogenic diet; proopiomelanocortin; saluresis

DESCRIPTION (provided by applicant): Variations in dietary sodium intake initiate integrated adjustments in neural and hormonal systems regulating sodium excretion by the kidneys in order to maintain overall sodium balance. These adjustments remain incompletely understood despite intensive study. In addition, a complex relationship exists between sodium balance and blood pressure such that high dietary sodium intake provokes hypertension in susceptible individuals. Studies from our laboratory have identified a previously unrecognized hormonal system which participates in the maintenance of sodium balance on a high sodium intake. This system involves the synthesis of the prohormone proopiomelanocortin (POMC) in the pituitary, and its processing into the secreted natriuretic peptide gamma-melanocyte stimulating hormone (gamma-MSH). This system is activated by a high sodium diet in rats, mice, and humans, and fails to respond to sodium loading in rodents with genetic forms of hypertension. We shall characterize the hypertension seen with dietary sodium loading in mice with gamma-MSH deficiency due to targeted disruption of the proconvertase 2 gene, necessary for processing of POMC into gamma-MSH, and establish that the hypertension is corrected by infusion of gamma-MSH. We shall also evaluate the consequences of inhibition of gamma-MSH release from the pituitary by dopaminergic stimulation in rats fed a high sodium diet, and test the effects of sodium loading in mice lacking melanocortin receptors with which gamma-MSH interacts. In addition, we shall characterize the nature and location of renal melanocortin receptors, and determine if their expression is altered by a high sodium diet. We shall determine if gamma-MSH acts centrally to inhibit sympathetic nervous outflow and lower blood pressure in hypertensive PC2 -/- mice on the high sodium diet. Finally, we shall examine the effects of high vs low sodium diets on blood pressure and plasma gamma-MSH concentration in normal subjects and patients with mild essential hypertension studied in a General Clinical Research Center to determine if this system functions in humans in a manner parallel to that in rodents and evaluate if individuals with salt-sensitive hypertension demonstrate blunted activation of the system. These studies should extend our understanding of the integrated regulation of sodium balance when challenged with a high sodium intake, and the relationship between sodium intake and the development of hypertension, by providing mechanistic insight into a novel and previously unrecognized system activated by high dietary sodium intake.

描述（由申请人提供）：饮食中钠摄入量的变化启动了综合调整的神经和荷尔蒙系统的调整，以调节肾脏的钠排泄，以维持整体钠平衡。 尽管进行了深入研究，但这些调整仍未完全理解。 此外，钠平衡与血压之间存在复杂的关系，使得饮食中的饮食中摄入量高会激发易感人群的高血压。 我们实验室的研究已经确定了先前未识别的激素系统，该系统参与了高钠摄入量的钠平衡。 该系统涉及垂体中的激太激素促蛋白酶素（POMC）的合成，并将其加工到分泌的纳替尼二肽肽γ-甲状腺细胞刺激激素（Gamma-MSH）中。 大鼠，小鼠和人类的高钠饮食激活该系统，并且无法应对具有高血压遗传形式的啮齿动物中的钠负荷。 我们将表征由于靶向破坏proconvertase 2基因而导致γ-MSH缺乏的小鼠中饮食中钠负荷所看到的高血压，这对于将POMC处理成γ-MSH所必需，并确定高血压通过输注γ-MSH的输注来纠正。 我们还将评估喂养高钠饮食的大鼠在垂体中抑制γ-MSH从垂体中释放的后果，并测试缺乏与黑色素质素受体相互作用的黑素性质子素受体的钠负荷的作用。 此外，我们将表征肾脏黑色皮质素受体的性质和位置，并确定它们的表达是否通过高钠饮食改变。 我们将确定γ-MSH在高钠饮食上高血压PC2 - / - 小鼠中的抑制交感神经流出和降低血压。 最后，我们将检查在普通临床研究中心中研究的正常受试者和患有轻度基本高血压的患者血压和血浆γ-MSH浓度对血压和血浆γ-MSH浓度的影响，以确定该系统是否在啮齿动物中与啮齿动物相似，并评估患有盐敏感性的患者是否表现出盐敏感性的系统。 这些研究应通过向高饮食钠摄入量高的新颖且未经认识的系统提供机械洞察力，从而扩展我们对钠平衡的综合调节，以及钠摄入量与高血压发展之间的关系，以及钠摄入量与高血压发展之间的关系。