Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells
Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells
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DOI：
10.1152/ajpendo.90264.2008
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发表时间：
2008-10-01
影响因子：
5.1
通讯作者：
Huang, Yufeng
中科院分区：
文献类型：
--
作者：
Zhang, Jiandong;Noble, Nancy A.;Huang, Yufeng
尽管血浆肾素原水平升高常见于糖尿病患者，并且与微血管并发症相关，但其病理作用（如果有的话）仍不清楚。肾素原/肾素与肾素原/肾素受体 [(p) RR] 结合可增强肾素裂解血管紧张素原的效率，并揭示肾素原催化活性。我们询问血浆肾素原是否可以通过受体结合在局部血管组织中被激活。免疫组织化学染色显示主动脉中 (p) RR 定位于血管平滑肌细胞 (VSMC)。将培养的大鼠VSMC与10(-7)M失活的肾素原一起孵育后，培养上清液获得了由血管紧张素原生成ANG I的能力，表明肾素原已被激活。当添加外源性血管紧张素原时，活化的肾素原促进培养的 VSMC 中血管紧张素的产生。针对 (p) RR 的小干扰 RNA (siRNA) 阻断了这种激活和随后的血管紧张素生成。单独的肾素原可诱导促纤维化分子纤溶酶原激活剂抑制剂 (PAI)-1 的 mRNA 和蛋白质呈剂量和时间依赖性增加，这种作用可被 siRNA 阻断，但不能被 ANG II 受体拮抗剂萨拉拉辛阻断。当无活性的肾素原和血管紧张素原与细胞一起孵育时，PAI-1 mRNA 增加了惊人的 54 倍，比单独使用肾素原时所见的增加高出 8 倍。 PAI-1 蛋白增加了 2.75 倍。这些效应可通过 siRNA + saralasin 治疗来阻断。我们得出结论，高浓度的肾素原与 VSMC 上的 (p) RR 结合并被激活。这种激活通过 ANG II 独立和依赖机制导致 PAI-1 表达增加。这些数据提供了一种机制，糖尿病中肾素原水平升高可能导致纤维化疾病的进展。
Although elevated plasma prorenin levels are commonly found in diabetic patients and correlate with microvascular complications, the pathological role of these increases, if any, remains unclear. Prorenin/renin binding to the prorenin/renin receptor [(p) RR] enhances the efficiency of angiotensinogen cleavage by renin and unmasks prorenin catalytic activity. We asked whether plasma prorenin could be activated in local vascular tissue through receptor binding. Immunohistochemical staining showing localization of the (p) RR in the aorta to vascular smooth muscle cells (VSMCs). After cultured rat VSMCs were incubated with 10(-7) M inactive prorenin, cultured supernatant acquired the ability to generate ANG I from angiotensinogen, indicating that prorenin had been activated. Activated prorenin facilitated angiotensin generation in cultured VSMCs when exogenous angiotensinogen was added. Small interfering RNA (siRNA) against the (p) RR blocked this activation and subsequent angiotensin generation. Prorenin alone induced dose- and time-dependent increases in mRNA and protein for the profibrotic molecule plasminogen activator inhibitor (PAI)-1, effects that were blocked by siRNA, but not by the ANG II receptor antagonist saralasin. When inactive prorenin and angiotensinogen were incubated with cells, PAI-1 mRNA increased a striking 54-fold, 8-fold higher than the increase seen with prorenin alone. PAI-1 protein increased 2.75-fold. These effects were blocked by treatment with siRNA + saralasin. We conclude that prorenin at high concentration binds the (p) RR on VSMCs and is activated. This activation leads to increased expression of PAI-1 via ANG II-independent and -dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may contribute to the progression of fibrotic disease.