Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system.
Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin-angiotensin system.
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DOI：
10.1016/j.bbrc.2009.10.121
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发表时间：
2009-12
影响因子：
3.1
通讯作者：
M. Uraoka;K. Ikeda;Y. Nakagawa;Masahiro Koide;Yoshiki Akakabe;Ritsuko Nakano-Kurimoto;Tomosaburo Takahashi;S. Matoba;H. Yamada;M. Okigaki;H. Matsubara
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文献类型：
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作者：
M. Uraoka;K. Ikeda;Y. Nakagawa;Masahiro Koide;Yoshiki Akakabe;Ritsuko Nakano-Kurimoto;Tomosaburo Takahashi;S. Matoba;H. Yamada;M. Okigaki;H. Matsubara
原肾素是一种无酶活性的前体肾素，尽管其与糖尿病微血管并发症的发生有关，但其在内皮细胞（EC）中的生物学功能尚不清楚。近年来，肾素（原）受体被鉴定，并发现了受体相关的原肾素系统，但其在内皮细胞中的表达和功能尚不清楚。在本研究中，我们发现，内皮细胞表达（原）肾素受体，并通过（原）肾素受体独立的肾素-血管紧张素系统（RAS）的前肾素引起ERK激活。原肾素刺激内皮细胞增殖、迁移和管腔形成，抑制血清和生长因子耗竭诱导的内皮细胞凋亡。MEK抑制剂可阻断肾素原的这些促血管生成作用，而AT 1受体拮抗剂或血管紧张素转换酶抑制剂则不能阻断这些作用。在体内新血管形成的基质胶塞植入到小鼠胁腹显着增强，其中显着的ERK激活检测EC。此外，稳定转染前肾素的肿瘤异种移植物表现出显著加速的生长速率，伴随着增强的肿瘤内新血管形成。我们的数据表明，RAS非依赖性（原）肾素受体介导的信号转导在调节内皮细胞功能以及新生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以及癌症的病理生理学。
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.