Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct
Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct
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DOI：
10.1152/ajprenal.00360.2015
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发表时间：
2016-02-15
影响因子：
4.2
通讯作者：
Prieto, Minolfa C.
中科院分区：
文献类型：
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作者：
Gonzalez, Alexis A.;Cifuentes-Araneda, Flavia;Prieto, Minolfa C.
肾素是在集管（CD）的主要细胞中合成的，在血管紧张素（ANG） ii依赖性高血压中，尽管肾小球旁肾素（JG）受到抑制，但它的产生通过cAMP增加。血管加压素是肾素血管紧张素系统（RAS）的效应激素之一，通过2型受体（V2R）激活cAMP/PKA/cAMP反应元件结合蛋白（CREB）途径和CD主要细胞中的水通道蛋白-2表达。因此，我们假设V2R的激活通过PKA/CREB增加肾素合成，独立于CD细胞中ANG II型1 （AT(1)）受体的激活。去氨加压素（DDAVP; 10(-6) M）是一种选择性V2R激动剂，在M-1 CD细胞系的细胞裂解物和细胞培养基中，肾素mRNA（类似于3倍）、促肾素（类似于1.5倍）和肾素（类似于2倍）增加。与DDAVP+H89 （PKA抑制剂）或CREB短发夹（sh） RNA共同治疗可阻止这种反应。H89还减弱了ddavp诱导的CREB磷酸化和核定位。在48小时缺水（WD）小鼠中，肾内髓质中泌乳素-肾素蛋白水平升高（类似于1.4倍和1.8倍）。在ACE抑制剂加AT(1)受体阻断的WD小鼠中，肾素mRNA和prorenin蛋白水平仍高于对照组，而肾素蛋白含量未发生变化。在M-1细胞中，ANG II或DDAVP增加了原肾素-肾素蛋白水平；然而，联合治疗没有进一步增加。这些结果表明，在CD中，V2R的激活通过独立于RAS的PKA/CREB途径刺激肾素合成，提示抗利尿激素在CD中调节肾素的关键作用。
Renin is synthesized in the principal cells of the collecting duct (CD), and its production is increased via cAMP in angiotensin (ANG) II-dependent hypertension, despite suppression of juxtaglomerular (JG) renin. Vasopressin, one of the effector hormones of the reninangiotensin system (RAS) via the type 2-receptor (V2R), activates the cAMP/PKA/cAMP response element-binding protein (CREB) pathway and aquaporin-2 expression in principal cells of the CD. Accordingly, we hypothesized that activation of V2R increases renin synthesis via PKA/CREB, independently of ANG II type 1 (AT(1)) receptor activation in CD cells. Desmopressin (DDAVP; 10(-6) M), a selective V2R agonist, increased renin mRNA (similar to 3-fold), prorenin (similar to 1.5-fold), and renin (similar to 2-fold) in cell lysates and cell culture media in the M-1 CD cell line. Cotreatment with DDAVP+H89 (PKA inhibitor) or CREB short hairpin (sh) RNA prevented this response. H89 also blunted DDAVP-induced CREB phosphorylation and nuclear localization. In 48-h water-deprived (WD) mice, prorenin-renin protein levels were increased in the renal inner medulla (similar to 1.4- and 1.8-fold). In WD mice treated with an ACE inhibitor plus AT(1) receptor blockade, renin mRNA and prorenin protein levels were still higher than controls, while renin protein content was not changed. In M-1 cells, ANG II or DDAVP increased prorenin-renin protein levels; however, there were no further increases by combined treatment. These results indicate that in the CD the activation of the V2R stimulates renin synthesis via the PKA/CREB pathway independently of RAS, suggesting a critical role for vasopressin in the regulation of renin in the CD.