Ray P E, Bruggeman L A, Horikoshi S, Aguilera G, Klotman P E
Laboratory of Developmental Biology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland.
Kidney Int. 1994 Jan;45(1):177-84. doi: 10.1038/ki.1994.21.
The renin-angiotensin system is activated during vascular development and injury. Furthermore, angiotensin II (Ang II) is a comitogen for fetal mesangial cells in vitro and it may be important in vascular smooth cell growth in disease states. Since fibronectin is an important extracellular matrix protein for vascular development and it too is overexpressed in the mesangium of diseased glomeruli, we explored the interrelationship of fibronectin and Ang II in fetal mesangial cell growth. In human fetal kidney, Ang II type 2 receptors (AT2) were detected in abundance by ex vivo autoradiography. When mesangial cells were isolated from fetal kidney and grown in culture, Ang II type 1 receptors (AT1) were also detected. To explore the mitogenic properties Ang II and fibronectin as well as the effects of Ang II on fibronectin metabolism, studies were performed in vitro, isolated from the potentially confounding variables of hemodynamic influence and circulating growth factors and cytokines. In vitro, mesangial cells expressed a single class of AT1 receptors that were not altered by growth on various substrates. Ang II (10(-7) M) significantly increased thymidine incorporation by confluent human fetal mesangial cells (twofold). When subconfluent, Ang II-stimulated proliferation was greater (fourfold). Ang II significantly increased cell-associated and secreted fibronectin as determined by immunoprecipitation at concentrations that also stimulate mitogenesis. Both of these Ang II-mediated responses were inhibited by the AT1 receptor antagonist DuP-753 (10(-5) M) but not by AT2 receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
肾素-血管紧张素系统在血管发育和损伤过程中被激活。此外，血管紧张素II（Ang II）在体外是胎儿系膜细胞的协同有丝分裂原，在疾病状态下其对血管平滑肌细胞生长可能很重要。由于纤连蛋白是血管发育的一种重要细胞外基质蛋白，且在患病肾小球系膜中也过度表达，我们探讨了纤连蛋白与Ang II在胎儿系膜细胞生长中的相互关系。在人胎儿肾脏中，通过离体放射自显影大量检测到血管紧张素II 2型受体（AT2）。当从胎儿肾脏分离系膜细胞并在培养中生长时，也检测到了血管紧张素II 1型受体（AT1）。为了探究Ang II和纤连蛋白的促有丝分裂特性以及Ang II对纤连蛋白代谢的影响，在体外进行了研究，排除了血流动力学影响以及循环生长因子和细胞因子等潜在混杂变量。在体外，系膜细胞表达单一类型的AT1受体，其不会因在各种基质上生长而改变。Ang II（10⁻⁷ M）显著增加汇合的人胎儿系膜细胞的胸苷掺入量（两倍）。当细胞未汇合时，Ang II刺激的增殖更大（四倍）。Ang II在刺激有丝分裂的浓度下，通过免疫沉淀测定，显著增加细胞相关和分泌的纤连蛋白。这两种Ang II介导的反应均被AT1受体拮抗剂DuP - 753（10⁻⁵ M）抑制，但不被AT2受体拮抗剂抑制。（摘要截短于250字）
