Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566, Japan.
Biochem Biophys Res Commun. 2009 Dec 25;390(4):1202-7. doi: 10.1016/j.bbrc.2009.10.121. Epub 2009 Oct 29.
Prorenin is an enzymatically inactive precursor of renin, and its biological function in endothelial cells (ECs) is unknown despite its relevance with the incidence of diabetic microvascular complications. Recently, (pro)renin receptor was identified, and the receptor-associated prorenin system has been discovered, whereas its expression as well as function in ECs remain unclear. In the present study, we found that ECs express the (pro)renin receptor, and that prorenin provoked ERK activation through (pro)renin receptor independently of the renin-angiotensin system (RAS). Prorenin stimulated the proliferation, migration and tube-formation of ECs, while it inhibited endothelial apoptosis induced by serum and growth factor depletion. MEK inhibitor abrogated these proangiogenic effects of prorenin, while AT1 receptor antagonist or angiotensin-converting enzyme inhibitor failed to block them. In vivo neovascularization in the Matrigel-plugs implanted into mouse flanks was significantly enhanced by prorenin, in which significant ERK activation was detected in ECs. Furthermore, tumor xenografts stably transfected with prorenin demonstrated the significantly accelerated growth rate concomitantly with enhanced intratumoral neovascularization. Our data demonstrated that the RAS-independent (pro)renin receptor-mediated signal transduction plays a pivotal role in the regulation of ECs function as well as in the neovascularization, and thus prorenin is potentially involved in the pathophysiology of diabetic microvascular complications as well as cancers.
原肾素是肾素的无酶前体，尽管它与糖尿病微血管并发症的发生有关，但内皮细胞（ECs）中其生物学功能尚不清楚。最近，（pro）肾素受体被鉴定出来，并且发现了受体相关的原肾素系统，而其在 ECs 中的表达和功能仍不清楚。在本研究中，我们发现 ECs 表达（pro）肾素受体，并且原肾素通过（pro）肾素受体独立于肾素-血管紧张素系统（RAS）引发 ERK 激活。原肾素刺激 ECs 的增殖、迁移和管状形成，同时抑制由血清和生长因子耗竭引起的内皮细胞凋亡。MEK 抑制剂阻断了原肾素的这些促血管生成作用，而 AT1 受体拮抗剂或血管紧张素转换酶抑制剂未能阻断这些作用。在向小鼠侧腹植入的 Matrigel 塞中，原肾素显著增强了新血管形成，在 ECs 中检测到显著的 ERK 激活。此外，稳定转染原肾素的肿瘤异种移植物表现出明显的生长速度加快，同时伴有肿瘤内新血管形成增强。我们的数据表明，RAS 独立的（pro）肾素受体介导的信号转导在调节 ECs 功能和新血管形成中起着关键作用，因此原肾素可能参与糖尿病微血管并发症和癌症的病理生理学。
