Role of GRK4 in the regulation of the renal ETB receptor in hypertension.
Role of GRK4 in the regulation of the renal ETB receptor in hypertension.
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GRK4 在高血压肾 ETB 受体调节中的作用
DOI：
10.1096/fj.201902552r
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Yang Y;Li M;Zou X;Chen C;Zheng S;Fu C;Chen K;Jose PA;Lan C;Liu Y
内皮素受体B型（ETBR）部分通过抑制肾钠转运来调节水和电解质平衡以及血压。我们的初步研究发现，ETBR介导的利尿和利钠功能在高血压中受损，但机制不明。G蛋白偶联受体激酶4（GRK 4）的活性持续增加，由表达增加或遗传变异（例如GRKγ 142 V）引起，部分通过持续磷酸化损害肾脏多巴胺D1受体功能，从而损害肾脏排泄钠负荷的能力。我们目前的研究发现，虽然肾ETBR的表达在Wistar-Kyoto（WKY）和自发性高血压大鼠（SHR）之间没有差异，但SHR的肾ETBR磷酸化水平较高。人（h）GRK 4 γ转基因小鼠的结果支持过度磷酸化在ETBR功能受损中的作用。在人（h）GRK 4 γ野生型（WT）小鼠中通过BQ 3020诱导的尿钠排泄刺激ETBR。然而，在hGRK 4 γ 142 V转基因小鼠中，肾脏ETBR过度磷酸化，ETBR介导的利钠和利尿作用不明显。ETBR和GRK 4在WKY和SHR的肾近曲小管（RPT）细胞中均存在共定位和共沉淀，但后者的共定位和共沉淀率高于前者。通过siRNA下调GRK 4的表达，ETBR对SHR RPT细胞Na+-K+-ATP酶活性的抑制作用得以恢复。在体内通过超声靶向微泡破坏下调肾脏GRK 4表达，减少ETBR磷酸化，恢复ETBR介导的钠尿和利尿作用。本研究提供了GRK 4通过调节肾脏ETBR功能参与高血压发病机制的机制。
The endothelin receptor type B (ETBR) regulates water and electrolyte balance and blood pressure, in part, by inhibiting renal sodium transport. Our preliminary study found that the ETBR-mediated diuresis and natriuresis are impaired in hypertension with unknown mechanism. Persistently increased activity of G protein-coupled receptor kinase 4 (GRK4), caused by increased expression or genetic variants (eg, GRKγ142V), impairs the ability of the kidney to excrete a sodium load, in part, by impairing renal dopamine D1 receptor function through persistent phosphorylation. Our present study found that although renal ETBR expression was not different between Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), renal ETBR phosphorylation was higher in SHRs. The role of hyper-phosphorylation in impaired ETBR-function was supported by results in human (h) GRK4γ transgenic mice. Stimulation of ETBR by BQ3020-induced natriuresis in human (h) GRK4γ wild-type (WT) mice. However, in hGRK4γ 142V transgenic mice, the renal ETBR was hyperphosphorylated and ETBR-mediated natriuresis and diuresis were not evident. There were co-localization and co-immunoprecipitation of ETBR and GRK4 in renal proximal tubule (RPT) cells from both WKY and SHRs but was greater in the latter than the former group. SiRNA-mediated downregulation of GRK4 expression, recovered the impaired inhibitory effect of ETBR on Na+-K+-ATPase activity in RPT cells from SHR. In vivo downregulation of renal GRK4 expression, via ultrasound-targeted microbubble destruction, decreased ETBR phosphorylation and restored ETBR-mediated natriuresis and diuresis in SHRs. This study provides a mechanism by which GRK4, via regulation of renal ETBR function, participates in the pathogenesis of hypertension.
影响因子：
5.4
作者：
Liu, Yan;Yang, Jian;Ren, Hongmei;He, Duofen;Pascua, Annabelle;Armando, M. Ines;Yang, Chengming;Zhou, Lin;Felder, Robin A.;Jose, Pedro A.;Zeng, Chunyu
通讯作者：
Zeng, Chunyu