Genetic disruption of γ-melanocyte-stimulationg hormone signaling leads to salt-sensitive hypertension in the mouse
Genetic disruption of γ-melanocyte-stimulationg hormone signaling leads to salt-sensitive hypertension in the mouse
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DOI：
10.1172/jci200316993
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发表时间：
2003-04-01
影响因子：
15.9
通讯作者：
Humphreys, MH
中科院分区：
文献类型：
--
作者：
Ni, XP;Pearce, D;Humphreys, MH
γ-促黑素细胞激素（gamma-MSH）是一种源自阿黑皮素原（POMC）N-末端区域的利钠肽。有证据表明，这可能是对低钠饮食（LSD）的协调反应的一部分。我们测试了HSD（8% NaCl）与LSD（0.07%）相比对小鼠平均动脉压（MAP）的影响，该小鼠具有靶向破坏PC 2基因（PC 2（-/-））或黑皮质素受体3基因（Mc 3r（-/-）; MSH受体），PC 2基因是将POMC加工成γ-MSH所必需的。在野生型小鼠中，HSD 1周与LSD小鼠相比没有改变MAP，但血浆γ-MSH免疫反应性是LSD值的两倍多。相比之下，在PC 2（-/-）小鼠中，LSD的MAP并不大于野生型小鼠，但血浆γ-MSH降低到野生型值的七分之一。在HSD，MAP上升到一个显着的高血压水平，而血浆γ-MSH浓度仍然严重抑制。HSD 1周后，静脉输注γ-MSH（0.2 pmol/min）30 min可使PC 2（-/-）小鼠的MAP从高血压水平降至正常水平;以相同速率输注α-MSH则无影响。向高血压小鼠侧脑室注射60 fmol的γ-MSH也使MAP降至正常。通过微渗泵腹腔注射稳定的γ-MSH类似物可预防PC 2（-/-）小鼠在摄入HSD时发生高血压。在靶向破坏Mc 3r基因的小鼠中，HSD也导致显著的高血压，伴有血浆γ-MSH水平升高;向这些小鼠输注外源性γ-MSH对MAP没有影响。这些结果强烈表明，PC 2依赖性加工POMC到γ-MSH是必要的正常反应的HSD。γ-MSH缺乏导致明显的盐敏感性高血压，外源性γ-MSH通过中枢作用部位迅速改善。以相同速率输注的α-MSH对MAP没有影响，表明高血压是POMC加工成γ-MSH受损的特定结果。Mc 3r的缺乏在HSD上产生γ-MSH抵抗和高血压。这些发现表明了一种新的途径介导的盐敏感性的血压。
The gamma-melanocyte-stimulating hormone (gamma-MSH) is a natriuretic peptide derived from the N-terminal region of proopiomelanocortin (POMC). Evidence suggests that it may be part of the coordinated response to a low-sodium diet (LSD). We tested the effect of the HSD (8% NaCl) compared with LSD (0.07%) on mean arterial pressure (MAP) in mice with targeted disruption of the PC2 gene (PC2(-/-)), necessary for processing of POMC into gamma-MSH, or the melanocortin receptor 3 gene (Mc3r(-/-); the receptor for MSH). In wild-type mice, HSD for 1 week did not alter MAP versus LSD mice, but plasma gamma-MSH immunoreactivity was more than double the LSD value. In contrast, in PC2(-/-) mice, MAP on the LSD was not greater than in wild-type mice, but plasma gamma-MSH was reduced to one-seventh the wild-type value. On the HSD, MAP rose to a markedly hypertensive level while plasma gamma-MSH concentration remained severely depressed. Intravenous infusion of gamma-MSH (0.2 pmol/min) for 30 min to PC2(-/-) mice after 1 week of HSD lowered MAP from hypertensive levels to normal; infusion of alpha-MSH at the same rate had no effect. injection of 60 fmol of gamma-MSH into the lateral cerebral ventricle of hypertensive mice also lowered MAP to normal. Administration of a stable analogue of gamma-MSH intra-abdominally by microosmotic pump to PC2(-/-) mice prevented the development of hypertension when ingesting the HSD. In mice with targeted disruption of the Mc3r gene, the HSD also led to marked hypertension accompanied by elevated plasma levels of gamma-MSH; infusion of exogenous gamma-MSH to these mice had no effect on MAP. These results strongly suggest that PC2-dependent processing of POMC into gamma-MSH is necessary for the normal response to the HSD. gamma-MSH deficiency results in marked salt-sensitive hypertension that is rapidly improved with exogenous gamma-MSH through a central site of action. a-MSH infused at the same rate had no effect on MAP, indicating that the hypertension is a specific consequence of impaired POMC processing into gamma-MSH. Absence of Mc3r produces gamma-MSH resistance and hypertension on the HSD. These findings demonstrate a novel pathway mediating salt-sensitivity of blood pressure.