Müller D N, Luft F C
Franz Volhard Clinic, Berlin, Germany.
Basic Res Cardiol. 1998;93 Suppl 2:7-14. doi: 10.1007/s003950050194.
The behavior of the circulating renin-angiotensin system is well known; however, the actions of renin and the generation of angiotensin (ANG) II at the tissue level are less appreciated. We have used rat models to study this issue. We examined the cleavage of human angiotensinogen to ANG I by human renin and its inhibition by a human renin inhibitor in an isolated perfused hindlimb preparation from rats which express the human angiotensinogen gene. With this model, we were able to show that renin acts at the site of the vascular wall, rather than in the lumen, to generate ANG I, which is subsequently converted to ANG II. Furthermore, the cleavage is specifically dependent on renin and not on other lysosomal proteases. The renin gene is present in the vascular wall; however, whether or not renin is generated locally to act locally, or whether renin is taken up from the circulation to act locally was not clear. We used the same strain of transgenic rats to test this issue and showed that renin can be taken up by cardiac or coronary vasculature tissue and induces long-lasting local ANG II generation. Locally formed ANG I was converted to ANG II more effectively than infused ANG I. We did additional studies to examine the conversion step from ANG I to ANG II in the vessel wall. We perfused hindlimbs from Sprague-Dawley rats with ANG I and observed ANG II production, which was linear over a 10,000-fold concentration range of ANG I. However, when we increased angiotensin converting enzyme (ACE) gene expression in the vascular bed, which also increased ACE tissue concentrations, we were nevertheless able to demonstrate increased ANG II production with ACE upregulation. Taken together, these results demonstrate (1) the cleavage of local angiotensinogen to ANG I within the vascular wall by renin, (2) renin uptake from the circulation to evoke that local effect, and (3) a potential regulatory effect by vascular tissue ACE on ANG II production in the vessel wall. The findings support the notion of localized renin-angiotensin system-related effects on vascular function and structure.
循环肾素-血管紧张素系统的行为已广为人知；然而，肾素在组织水平的作用以及血管紧张素（ANG）II的生成却较少受到关注。我们使用大鼠模型来研究这个问题。我们在表达人血管紧张素原基因的大鼠离体灌注后肢制备物中，检测了人肾素将人血管紧张素原裂解为ANG I的过程以及人肾素抑制剂对其的抑制作用。利用这个模型，我们能够证明肾素在血管壁部位而非管腔内起作用，生成ANG I，随后ANG I被转化为ANG II。此外，这种裂解特异性地依赖于肾素，而不依赖于其他溶酶体蛋白酶。肾素基因存在于血管壁中；然而，肾素是在局部生成并在局部起作用，还是从循环中摄取后在局部起作用尚不清楚。我们使用同一品系的转基因大鼠来测试这个问题，结果表明肾素可被心脏或冠状动脉血管组织摄取，并诱导持久的局部ANG II生成。局部形成的ANG I比注入的ANG I更有效地转化为ANG II。我们还进行了额外的研究，以检查血管壁中从ANG I到ANG II的转化步骤。我们用ANG I灌注Sprague-Dawley大鼠的后肢，并观察到ANG II的产生，在ANG I浓度范围达10000倍时呈线性关系。然而，当我们增加血管床中血管紧张素转换酶（ACE）基因的表达，这也会增加ACE组织浓度时，我们仍然能够证明随着ACE上调ANG II的产生增加。综上所述，这些结果表明：（1）肾素在血管壁内将局部血管紧张素原裂解为ANG I；（2）肾素从循环中摄取以引发局部效应；（3）血管组织ACE对血管壁中ANG II产生具有潜在的调节作用。这些发现支持了肾素-血管紧张素系统对血管功能和结构具有局部相关效应的观点。
