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）：膳食钠摄入量的变化会启动调节肾脏钠排泄的神经和激素系统的综合调整，以维持总体钠平衡。 尽管进行了深入研究，但这些调整仍未完全被理解。 此外，钠平衡与血压之间存在复杂的关系，因此高膳食钠摄入量会引发易感人群的高血压。 我们实验室的研究发现了一种以前未被认识的激素系统，该系统参与高钠摄入量时维持钠平衡。 该系统涉及垂体中激素原阿片黑皮质素 (POMC) 的合成，并将其加工成分泌型利尿钠肽 γ-黑素细胞刺激激素 (γ-MSH)。 该系统由大鼠、小鼠和人类的高钠饮食激活，并且无法对患有遗传性高血压的啮齿动物的钠负荷做出反应。 我们将描述由于定向破坏原转化酶 2 基因而导致 γ-MSH 缺乏的小鼠中饮食钠负荷所见的高血压，该基因是将 POMC 加工成 γ-MSH 所必需的，并确定通过输注 γ-MSH 可以纠正高血压。 我们还将评估高钠饮食大鼠中多巴胺能刺激抑制垂体释放 γ-MSH 的后果，并测试钠负荷对缺乏与 γ-MSH 相互作用的黑皮质素受体的小鼠的影响。 此外，我们将描述肾黑皮质素受体的性质和位置，并确定它们的表达是否会因高钠饮食而改变。 我们将确定 γ-MSH 是否在高钠饮食的高血压 PC2 -/- 小鼠中发挥中枢抑制交感神经流出和降低血压的作用。 最后，我们将在一般临床研究中心研究的正常受试者和轻度原发性高血压患者中检查高钠饮食与低钠饮食对血压和血浆 γ-MSH 浓度的影响，以确定该系统在人类中是否以平行的方式发挥作用与啮齿类动物相比，并评估患有盐敏感性高血压的个体是否表现出该系统的激活迟缓。 这些研究应该通过提供对由高钠摄入量激活的新颖且先前未被认识的系统的机制见解，应该扩展我们对高钠摄入量挑战时钠平衡的综合调节以及钠摄入量与高血压发展之间关系的理解。 。