Sparks Matthew A, Stegbauer Johannes, Chen Daian, Gomez Jose A, Griffiths Robert C, Azad Hooman A, Herrera Marcela, Gurley Susan B, Coffman Thomas M
Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina;
Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, North Carolina; Department of Nephrology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany;
J Am Soc Nephrol. 2015 Dec;26(12):2953-62. doi: 10.1681/ASN.2014080816. Epub 2015 Apr 8.
Inappropriate activation of the type 1A angiotensin (AT1A) receptor contributes to the pathogenesis of hypertension and its associated complications. To define the role for actions of vascular AT1A receptors in BP regulation and hypertension pathogenesis, we generated mice with cell-specific deletion of AT1A receptors in smooth muscle cells (SMKO mice) using Loxp technology and Cre transgenes with robust expression in both conductance and resistance arteries. We found that elimination of AT1A receptors from vascular smooth muscle cells (VSMCs) caused a modest (approximately 7 mmHg) yet significant reduction in baseline BP and exaggerated sodium sensitivity in mice. Additionally, the severity of angiotensin II (Ang II)-dependent hypertension was dramatically attenuated in SMKO mice, and this protection against hypertension was associated with enhanced urinary excretion of sodium. Despite the lower BP, acute vasoconstrictor responses to Ang II in the systemic vasculature were largely preserved (approximately 80% of control levels) in SMKO mice because of exaggerated activity of the sympathetic nervous system rather than residual actions of AT1B receptors. In contrast, Ang II-dependent responses in the renal circulation were almost completely eliminated in SMKO mice (approximately 5%-10% of control levels). These findings suggest that direct actions of AT1A receptors in VSMCs are essential for regulation of renal blood flow by Ang II and highlight the capacity of Ang II-dependent vascular responses in the kidney to effect natriuresis and BP control.
1A型血管紧张素（AT1A）受体的不适当激活会导致高血压及其相关并发症的发病机制。为了确定血管AT1A受体在血压调节和高血压发病机制中的作用，我们使用Loxp技术和在电导动脉和阻力动脉中均有强大表达的Cre转基因，培育出平滑肌细胞中AT1A受体细胞特异性缺失的小鼠（SMKO小鼠）。我们发现，从小鼠血管平滑肌细胞（VSMC）中消除AT1A受体可导致基线血压适度（约7 mmHg）但显著降低，并使小鼠对钠的敏感性增强。此外，SMKO小鼠中依赖血管紧张素II（Ang II）的高血压严重程度显著减轻，这种对高血压的保护作用与尿钠排泄增加有关。尽管血压较低，但由于交感神经系统活动增强而非AT1B受体的残余作用，SMKO小鼠全身血管系统对Ang II的急性血管收缩反应在很大程度上得以保留（约为对照水平的80%）。相比之下，SMKO小鼠肾循环中依赖Ang II的反应几乎完全消除（约为对照水平的5%-10%）。这些发现表明，VSMC中AT1A受体的直接作用对于Ang II调节肾血流量至关重要，并突出了肾中依赖Ang II的血管反应影响尿钠排泄和血压控制的能力。
