Galley Joseph C, Hahn Scott A, Miller Megan P, Durgin Brittany G, Jackson Edwin K, Stocker Sean D, Straub Adam C
Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Br J Pharmacol. 2022 Jun;179(11):2490-2504. doi: 10.1111/bph.15522. Epub 2021 Jun 9.
Reduced renal blood flow triggers activation of the renin-angiotensin-aldosterone system (RAAS) leading to renovascular hypertension. Renal vascular smooth muscle expression of the NO receptor, soluble GC (sGC), modulates the vasodilator response needed to control renal vascular tone and blood flow. Here, we tested if angiotensin II (Ang II) affects sGC expression via an AT receptor-forkhead box subclass O (FoxO) transcription factor dependent mechanism.
Using a murine two-kidney-one-clip (2K1C) renovascular hypertension model, we measured renal artery vasodilatory function and sGC expression. Additionally, we conducted cell culture studies using rat renal pre-glomerular smooth muscle cells (RPGSMCs) to test the in vitro mechanistic effects of Ang II treatment on sGC expression and downstream function.
Contralateral, unclipped renal arteries in 2K1C mice showed increased NO-dependent vasorelaxation compared to sham control mice. Immunofluorescence studies revealed increased sGC protein expression in 2K1C contralateral renal arteries over sham controls. RPGSMCs treated with Ang II caused a significant up-regulation of sGC mRNA and protein expression as well as downstream sGC-dependent signalling. Ang II signalling effects on sGC expression occurred through an AT receptor and FoxO transcription factor-dependent mechanism at both the mRNA and protein expression levels.
Renal artery smooth muscle, in vivo and in vitro, up-regulates expression of sGC following RAAS activity. In both cases, up-regulation of sGC leads to increased downstream cGMP signalling, suggesting a previously unrecognized protective mechanism to improve renal blood flow in the uninjured contralateral renal artery.
This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.
肾血流量减少会触发肾素-血管紧张素-醛固酮系统（RAAS）的激活，进而导致肾血管性高血压。肾血管平滑肌中一氧化氮（NO）受体可溶性鸟苷酸环化酶（sGC）的表达，调节着控制肾血管张力和血流量所需的血管舒张反应。在此，我们测试了血管紧张素II（Ang II）是否通过AT受体-叉头框O亚类（FoxO）转录因子依赖性机制影响sGC的表达。
使用小鼠双肾单夹（2K1C）肾血管性高血压模型，我们测量了肾动脉的血管舒张功能和sGC的表达。此外，我们使用大鼠肾小体前平滑肌细胞（RPGSMC）进行细胞培养研究，以测试Ang II处理对sGC表达及其下游功能的体外机制性影响。
与假手术对照小鼠相比，2K1C小鼠的对侧未夹闭肾动脉显示出NO依赖性血管舒张增加。免疫荧光研究显示，与假手术对照相比，2K1C对侧肾动脉中sGC蛋白表达增加。用Ang II处理的RPGSMC导致sGC mRNA和蛋白表达以及下游sGC依赖性信号传导显著上调。Ang II信号对sGC表达的影响在mRNA和蛋白表达水平上均通过AT受体和FoxO转录因子依赖性机制发生。
体内和体外的肾动脉平滑肌在RAAS激活后会上调sGC的表达。在这两种情况下，sGC的上调都会导致下游环磷酸鸟苷（cGMP）信号传导增加，这表明存在一种先前未被认识的保护机制，可改善未受损对侧肾动脉的肾血流量。
本文是关于细胞生长与存活中cGMP信号传导的主题系列文章的一部分。要查看本部分的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc。
