Protective role of AgRP neuron's PDK1 against salt-induced hypertension.
Protective role of AgRP neuron's PDK1 against salt-induced hypertension.
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DOI：
10.1016/j.bbrc.2018.04.192
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发表时间：
2018-06
影响因子：
3.1
通讯作者：
Boyang Zhang;M. Nakata;Ming-you Lu;J. Nakae;T. Okada;W. Ogawa;T. Yada
中科院分区：
文献类型：
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作者：
Boyang Zhang;M. Nakata;Ming-you Lu;J. Nakae;T. Okada;W. Ogawa;T. Yada
在下丘脑弓状核（ARC），食欲相关肽（AgRP）神经元调节摄食行为和能量稳态。AgRP神经元中的3-磷酸肌醇依赖性蛋白激酶-1（PDK 1）作为瘦素和胰岛素的主要信号分子，瘦素和胰岛素是调节进食行为、能量稳态和循环的激素。然而，目前尚不清楚AGRP神经元中的PDK 1是否也参与血压的调节。本研究通过建立和分析AgRP神经元特异性PDK 1基因敲除（Agrp-Pdk 1flox/flox）小鼠来探讨其作用，并分析高盐饮食对KO和WT小鼠血压的影响。在高盐饮食喂养下，Agrp-Pdk 1flox/mix小鼠的收缩压（SBP）显著高于Agrp-Crem小鼠。当高盐饮食转换为低盐饮食时，Agrp-Pdk 1flox/mouse小鼠的收缩压在1周内恢复到Agrp-Cremouse的基础水平。Agrp-Pdk 1flox/cirrhosis小鼠尿去甲肾上腺素排泄量和下丘脑室旁核（PVN）NUCB 2 mRNA表达显著增加。而且，室旁核中NUCB 2的沉默抵消了尿去甲肾上腺素排泄和SBP的升高。这些结果表明，PDK 1在AgRP神经元中通过防止PVN nesfatin-1神经元的过度激活来对抗高盐饮食诱导的高血压的新作用。
In the hypothalamic arcuate nucleus (ARC), orexigenic agouti-related peptide (AgRP) neurons regulate feeding behavior and energy homeostasis. The 3-phosphoinositide-dependent protein kinase-1 (PDK1) in AgRP neurons serves as a major signaling molecule for leptin and insulin, the hormones regulating feeding behavior, energy homeostasis and circulation. However, it is unclear whether PDK1 in AGRP neurons is also involved in regulation of blood pressure. This study explored it by generating and analyzing AgRP neuron-specific PDK1 knockout (Agrp-Pdk1flox/flox) mice and effect of high salt diet on blood pressure in KO and WT mice was analyzed. Under high salt diet feeding, systolic blood pressure (SBP) ofAgrp-Pdk1flox/floxmice was significantly elevated compared toAgrp-Cremice. When the high salt diet was switched to control low salt diet, SBP ofAgrp-Pdk1flox/floxmice returned to the basal level observed inAgrp-Cremice within 1 week. InAgrp-Pdk1flox/floxmice, urinary noradrenalin excretion and NUCB2 mRNA expression in hypothalamic paraventricular nucleus (PVN) were markedly upregulated. Moreover, silencing of NUCB2 in the PVN counteracted the rises in urinary noradrenalin excretions and SBP. These results demonstrate a novel role of PDK1 in AgRP neurons to counteract the high salt diet-induced hypertension by preventing hyperactivation of PVN nesfatin-1 neurons.