Supplemental Digital Content is available in the text. We have previously reported that in salt-resistant rat phenotypes brain, Gαi2 (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) Gαi2 proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi2 oligodeoxynucleotide, we show that PVN-specific Gαi2 proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi2 oligodeoxynucleotide 18±4; P<0.05) via a renal nerve-dependent mechanism. Furthermore, in response to chronically elevated dietary sodium intake, PVN-specific Gαi2 proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi2 oligodeoxynucleotide 147±3; P<0.05). This protective pathway involves activation of PVN Gαi2 signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi2 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 Gαi2 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 Gαi2 proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension.

中文翻译：

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下丘脑室旁核 Gαi 2（鸟嘌呤核苷酸结合蛋白α抑制活性多肽 2）蛋白质介导的肾脏神经控制和血压的盐敏感性


文本中提供了补充数字内容。我们之前报道过，在耐盐大鼠表型大脑中，Gαi2（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）Gαi2蛋白对血压盐敏感性的影响尚不清楚。在这里，通过双侧 PVN 施用靶向 Gαi2 寡脱氧核苷酸，我们表明需要 PVN 特异性 Gαi2 蛋白来促进对急性容量扩张的完全排钠反应（峰值排钠 [μeq/min] 乱序（SCR）寡脱氧核苷酸 41±3与Gαi2寡脱氧核苷酸18±4相比；P<0.05)通过肾神经依赖性机制。此外，为了应对长期升高的膳食钠摄入量，PVN 特异性 Gαi2 蛋白对于对抗肾神经依赖性盐敏感性高血压至关重要（平均动脉压 [mm Hg] 8% NaCl；SCR 寡脱氧核苷酸 128±2 与 Gαi2 寡脱氧核苷酸 147± 3；P<0.05）。该保护途径涉及激活 PVN Gαi2 信号通路，介导对血管和肾脏的交感神经抑制（肾去甲肾上腺素 [pg/mg] 8% NaCl；SCR 寡脱氧核苷酸 375±39 对比 Gαi2 寡脱氧核苷酸 850±27；P<0.05）和抑制氯化钠协同转运蛋白的活性评估为氢氯噻嗪的峰值尿钠排泄。此外，通过 FosB 免疫组织化学评估，中枢寡脱氧核苷酸介导的 Gαi2 蛋白下调可阻止 PVN 小细胞神经元激活，以响应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 个 GNAI2 单核苷酸多态性 (SNP) (rs2298952，P=0。041； rs4547694，P=0.017）与原发性高血压显着相关。总的来说，我们的数据表明选择性靶向和激活 PVN Gαi2 蛋白是治疗盐敏感性高血压的一种新方法。