Angiotensin II type 1 receptor-associated protein: a novel modulator of angiotensin II actions in the nephron.
Angiotensin II type 1 receptor-associated protein: a novel modulator of angiotensin II actions in the nephron.
复制标题
血管紧张素 II 1 型受体相关蛋白：肾单位血管紧张素 II 作用的新型调节剂。
DOI：
10.1161/hypertensionaha.113.01150
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Gonzalez-Villalobos,RomerA
中科院分区：
文献类型：
--
作者：
Giani,JorgeF;Fuchs,Sebastien;Gonzalez-Villalobos,RomerA
此外，在他们的分析中，远端肾单位是表达最高的部位。造成这种差异的原因尚不清楚，这应该是未来研究的课题。第二个问题涉及 ATRAP 对转基因小鼠基线血压缺乏影响。作者认为 ATRAP 仅在病理条件下才重要，但缺乏对此的机制解释。第三个问题是，过表达 ATRAP 对 NaCl 协同转运蛋白或上皮钠通道的实际活性（即对特定阻断剂的体内反应）的影响尚未评估。第四，如果转基因主要在远端肾单位中过度表达，那么它可能处于区域特异性增强子的控制之下。因此，转基因插入可能破坏了相应的基因座及其生理作用。最后也是最重要的是，非常高的 ATRAP 表达（远端肾小管中 mRNA 增加 33 倍，总肾匀浆中蛋白质增加 10 倍）对于减少对 Ang II 的反应是必要的，这一事实表明 ATRAP 的影响可能很小。不管之前的观察结果如何，Wakui 等人的研究强调了肾脏在 Ang II 的高血压反应中的巨大影响，同时强调了 ATRAP 作为负调节剂的潜力。作者提出了有趣的证据，证明 ATRAP 对 Ang II 作用的调节作用，以增加肾单位中钠的亲和力。这些结果为支持肾单位不同部分表达的 AT1R 在长期血压调节中发挥重要作用提供了越来越多的证据。 9, 10 关于 ATRAP 如何影响 AT1R 信号传导的现有证据和未来细节可能有助于更全面地了解 Ang II 调节肾功能的作用。最后，ATRAP 对其他肾脏过程的可能影响也很有趣。例如，人们越来越认识到肾内 RAS 的不当激活是高血压的重要原因。 10 然而，ATRAP 对局部 Ang II 库的影响尚不清楚。只有时间才能证明 ATRAP 表达的药理学操作是否有用。最终，最近 ATRAP 的发现及其作用的持续阐明提醒我们，我们不应该假设掌握了 Ang II 在肾脏生理学和高血压中作用的完整情况。
Moreover, in their analyses, the distal nephron is the site of highest expression. The reason for such difference is unknown, and it should be a topic for future investigation. The second issue deals with the lack of an ATRAP effect on baseline blood pressure of the transgenic mice. The authors suggest that ATRAP is only important in pathological conditions, but a mechanistic explanation for this is missing. The third issue is that the impact of overexpressing ATRAP on the actual activity of NaCl cotransporter or epithelial sodium channel (ie, in vivo response to specific blockers) was not evaluated. Fourth, if the transgene is overexpressed predominantly in the distal nephron, it follows that it is probably under the control of a region-specific enhancer. Hence, it is possible that the transgene insertion disrupted the corresponding locus and its physiological role. Finally and most importantly, the fact that a very high ATRAP expression (33-fold mRNA increase in distal tubules and 10-fold protein increases in total kidney homogenates) was necessary to reduce the response to Ang II suggests that ATRAP effects may be minor. Regardless of the previous observations, the study by Wakui et al5 emphasizes the tremendous impact of the kidneys in the hypertensive response to Ang II, while highlighting the potential of ATRAP as a negative modulator. The authors present interesting evidence for the tuning down effect ofATRAP on Ang II actions to increase sodium avidity in the nephron. These results add to the mounting evidence in favor of an important role of AT1Rs expressed in various segments of the nephron in long-term blood pressure regulation. 9, 10 The presented evidence and future details on how ATRAP affects AT1R signaling may lead to a more comprehensive understanding of Ang II actions to regulate renal function. Finally, the possible effect of ATRAP on other renal processes is also intriguing. For instance, it is increasingly recognized that inappropriate activation of the intrarenal RAS is an important cause of hypertension. 10 However, the effects of ATRAP on the local pool of Ang II are unknown. Only time will tell whether there is any usefulness in the pharmacological manipulation of ATRAP expression. Ultimately, the recent discovery of ATRAP and the ongoing elucidation of its effects remind us that we should not assume to possess the complete picture of Ang II actions in renal physiology and hypertension.