Carmichael Casey Y, Kuwabara Jill T, Pascale Crissey L, Moreira Jesse D, Mahne Sarah E, Kapusta Daniel R, Rosene Douglas L, Williams Jonathan S, Cunningham J Thomas, Wainford Richard D
From the Department of Pharmacology and Experimental Therapeutics and The Whitaker Cardiovascular Institute (C.Y.C., J.T.K., J.D.M., S.E.M., R.D.W.), Boston University School of Medicine, MA.
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA (C.L.P., D.R.K.).
Hypertension. 2020 Apr;75(4):1002-1011. doi: 10.1161/HYPERTENSIONAHA.119.13777. Epub 2020 Mar 9.
We have previously reported that in salt-resistant rat phenotypes brain, Gαi (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) Gαi proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi oligodeoxynucleotide, we show that PVN-specific Gαi proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi oligodeoxynucleotide 18±4; <0.05) via a renal nerve-dependent mechanism. Furthermore, in response to chronically elevated dietary sodium intake, PVN-specific Gαi proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi oligodeoxynucleotide 147±3; <0.05). This protective pathway involves activation of PVN Gαi signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi oligodeoxynucleotide 850±27; <0.05) and suppression of the activity of the sodium chloride cotransporter assessed as peak natriuresis to hydrochlorothiazide. Additionally, central oligodeoxynucleotide-mediated Gαi 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 single nucleotide polymorphism (SNP) (rs2298952, =0.041; rs4547694, =0.017) significantly correlate with essential hypertension. Collectively, our data suggest that selective targeting and activation of PVN Gαi proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension.
我们之前报道过，在抗盐大鼠表型的大脑中，Gαi（鸟嘌呤核苷酸结合蛋白α抑制活性多肽2）蛋白对于维持血压和钠平衡是必需的。然而，下丘脑室旁核（PVN）的Gαi蛋白对血压盐敏感性的影响尚不清楚。在此，通过向双侧PVN注射靶向Gαi的寡脱氧核苷酸，我们发现PVN特异性Gαi蛋白通过肾神经依赖性机制促进对急性容量扩张的完全利钠反应（峰值利钠[微当量/分钟]，乱序（SCR）寡脱氧核苷酸为41±3，而Gαi寡脱氧核苷酸为18±4；<0.05）。此外，对于长期升高的饮食钠摄入，PVN特异性Gαi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[毫米汞柱]，8%氯化钠；SCR寡脱氧核苷酸为128±2，而Gαi寡脱氧核苷酸为147±3；<0.05）。这种保护途径涉及激活PVN Gαi信号通路，该通路介导对血管和肾脏的交感神经抑制（肾去甲肾上腺素[皮克/毫克]，8%氯化钠；SCR寡脱氧核苷酸为375±39，而Gαi寡脱氧核苷酸为850±27；<0.05）以及抑制以对氢氯噻嗪的峰值利钠评估的氯化钠共转运体的活性。此外，通过FosB免疫组织化学评估，中枢寡脱氧核苷酸介导的Gαi蛋白下调可防止PVN小细胞神经元在饮食盐摄入增加时被激活。在我们对英国生物银行数据集的分析中，观察到2个单核苷酸多态性（SNP）（rs2298952，P = 0.041；rs4547694，P = 0.017）与原发性高血压显著相关。总体而言，我们的数据表明，选择性靶向和激活PVN Gαi蛋白是治疗盐敏感性高血压的一种新的治疗方法。
