gamma-MSH and Sodium Metabolism

描述(由申请人提供)：饮食钠摄入量的变化启动了神经和激素系统的综合调整，以调节肾脏的钠排泄，以维持整体钠平衡。尽管进行了深入的研究，但这些调整仍然没有完全被理解。此外，钠平衡和血压之间存在复杂的关系，以至于饮食中高钠摄入量会在易感人群中引发高血压。我们实验室的研究已经确定了一种以前未被认识到的激素系统，它参与了高钠摄入时维持钠平衡的过程。这一系统包括在脑下垂体合成前阿片黑素皮质素(POMC)，并将其加工成分泌的钠尿肽γ-黑素细胞刺激素(γ-MSH)。在大鼠、小鼠和人类中，这个系统被高钠饮食激活，而在患有遗传性高血压的啮齿动物中，该系统对钠负荷没有反应。我们将表征饮食钠负荷引起的由于原转换酶2基因的靶向中断而导致的伽马-MSH缺乏症小鼠的高血压，这是将POMC加工成伽马-MSH所必需的，并确定通过输注伽马-MSH来纠正高血压。我们还将评估在喂养高钠饮食的大鼠中，多巴胺能刺激抑制伽马-MSH释放的后果，并测试钠负荷对缺乏与伽马-MSH相互作用的黑素皮质素受体的小鼠的影响。此外，我们还将确定肾脏黑素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。我们将确定伽马-MSH是否在高钠饮食下抑制交感神经外流和降低高血压PC2-/-小鼠的血压方面起中枢作用。最后，我们将检查高钠饮食和低钠饮食对正常受试者和在普通临床研究中心研究的轻度高血压患者的血压和血浆伽马-MSH浓度的影响，以确定这一系统在人类中的功能是否与啮齿动物的功能相似，并评估盐敏感型高血压患者是否表现出该系统的钝化激活。这些研究应该扩大我们对高钠摄入量挑战时钠平衡的综合调节的理解，以及钠摄入量与高血压发展之间的关系，通过提供对高饮食钠摄入量激活的新的和以前未知的系统的机械性洞察。

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.