gamma-MSH and Sodium Metabolism

描述（由申请方提供）：膳食钠摄入量的变化启动神经和激素系统的综合调整，调节肾脏的钠排泄，以维持总体钠平衡。 尽管进行了深入的研究，这些调整仍然没有完全理解。 此外，钠平衡与血压之间存在复杂的关系，因此高膳食钠摄入会引起易感个体的高血压。 我们实验室的研究已经确定了一个以前未被认识到的激素系统，该系统参与维持高钠摄入量的钠平衡。 该系统涉及垂体中激素原阿黑皮素原（POMC）的合成，以及其加工成分泌的利钠肽γ-黑素细胞刺激激素（γ-MSH）。 该系统在大鼠、小鼠和人类中被高钠饮食激活，而在具有遗传形式的高血压的啮齿动物中对钠负荷没有反应。 我们将描述由于前转化酶2基因的靶向破坏导致γ-MSH缺乏的小鼠中饮食钠负荷所观察到的高血压，这是将POMC加工成γ-MSH所必需的，并确定高血压通过输注γ-MSH得到纠正。 我们还将评估在高钠饮食喂养的大鼠中通过多巴胺能刺激抑制垂体释放γ-MSH的后果，并在缺乏与γ-MSH相互作用的黑皮质素受体的小鼠中测试钠负荷的影响。 此外，我们将描述肾脏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是否通过中枢作用抑制高钠饮食的高血压PC 2-/-小鼠的交感神经流出和降低血压。 最后，我们将检查高钠饮食与低钠饮食对正常受试者和在综合临床研究中心研究的轻度原发性高血压患者的血压和血浆γ-MSH浓度的影响，以确定该系统在人类中是否以与啮齿动物平行的方式发挥作用，并评估盐敏感性高血压患者是否表现出该系统的钝化激活。 这些研究应该扩展我们对高钠摄入挑战时钠平衡的综合调节的理解，以及钠摄入与高血压发展之间的关系，通过提供对高膳食钠摄入激活的一种新的和以前未被认识的系统的机制见解。

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.