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首页> 外文期刊>Hypertension: An Official Journal of the American Heart Association >Hypothalamic Paraventricular Nucleus G alpha i(2) (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure
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Hypothalamic Paraventricular Nucleus G alpha i(2) (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure

机译：下丘脑椎间盘核α1（2）（鸟嘌呤核苷酸结合蛋白α抑制活性多肽2）蛋白介导的肾脏神经控制和血压的盐敏感性

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We have previously reported that in salt-resistant rat phenotypes brain, G alpha i(2) (guanine nucleotide-binding protein alpha inhibiting activity polypeptide 2) proteins are required to maintain blood pressure and sodium balance. However, the impact of hypothalamic paraventricular nucleus (PVN) G alpha i(2) proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted G alpha i(2) oligodeoxynucleotide, we show that PVN-specific G alpha i(2) proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [mu eq/min] scrambled (SCR) oligodeoxynucleotide 41 +/- 3 versus G alpha i(2) oligodeoxynucleotide 18 +/- 4; P<0.05) via a renal nerve-dependent mechanism. Furthermore, in response to chronically elevated dietary sodium intake, PVN-specific G alpha i(2) proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128 +/- 2 versus G alpha i(2) oligodeoxynucleotide 147 +/- 3; P<0.05). This protective pathway involves activation of PVN G alpha i(2) signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375 +/- 39 versus G alpha i(2) oligodeoxynucleotide 850 +/- 27; P<0.05) and suppression of the activity of the sodium chloride cotransporter assessed as peak natriuresis to hydrochlorothiazide. Additionally, central oligodeoxynucleotide-mediated G alpha i(2) protein downregulation prevented PVN parvocellular neuron activation, assessed by FosB immunohistochemistry, in response to increased dietary salt intake. In our analysis of the UK BioBank data set, it was observed that 2 GNAI2 single nucleotide polymorphism (SNP) (rs2298952, P=0.041; rs4547694, P=0.017) significantly correlate with essential hypertension. Collectively, our data suggest that selective targeting and activation of PVN G alpha i(2) proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension.
机译：我们之前报道过，在耐盐大鼠的脑表型中，Gαi（2）（鸟嘌呤核苷酸结合蛋白α抑制活性多肽2）蛋白是维持血压和钠平衡所必需的。然而，下丘脑室旁核（PVN）Gαi（2）蛋白对血压盐敏感性的影响尚不清楚。在这里，通过双侧PVN给药靶向性Gαi（2）寡核苷酸，我们表明PVN特异性Gαi（2）蛋白需要促进急性容量扩张时的完全利钠肽反应（峰值钠尿[mu eq/min]扰码（SCR）寡核苷酸41+/-3与Gαi（2）寡核苷酸18+/-4；P<0.05），通过肾神经依赖机制。此外，在长期增加饮食钠摄入量的情况下，PVN特异性Gαi（2）蛋白对于对抗肾神经依赖性盐敏感性高血压（平均动脉压[mm Hg]8%NaCl；SCR寡核苷酸128+/-2与Gαi（2）寡核苷酸147+/-3；P＜0.05）。这种保护性途径涉及PVN Gαi（2）信号通路的激活，其介导血管和肾脏的交感抑制（肾去甲肾上腺素[pg/mg]8%NaCl；SCR寡脱氧核苷酸375+/-39与Gαi（2）寡脱氧核苷酸850+/-27；P<0.05）和氯化钠共转运蛋白活性的抑制被评估为对氢氯噻嗪的利钠肽峰值。此外，通过FosB免疫组织化学评估，中枢寡核苷酸介导的Gαi（2）蛋白下调阻止了PVN小细胞神经元的激活，以应对饮食盐摄入量的增加。在我们对英国生物银行数据集的分析中，观察到2 GNAI2单核苷酸多态性（SNP）（rs2298952，P=0.041；rs4547694，P=0.017）与原发性高血压显著相关。总之，我们的数据表明，选择性靶向和激活PVN Gαi（2）蛋白是治疗盐敏感性高血压的一种新的治疗方法。

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