Renin increases mesangial cell transforming growth factor-β1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms
Renin increases mesangial cell transforming growth factor-β1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms
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DOI：
10.1038/sj.ki.5000011
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发表时间：
2006-01-01
影响因子：
19.6
通讯作者：
Border, W
中科院分区：
文献类型：
--
作者：
Huang, Y;Wongamorntham, S;Border, W
最近的证据表明，肾素-血管紧张素系统的组分和纤维化的关键介质之间存在强烈的相互作用，这使我们假设，肾素，独立于其酶促作用，以增强血管紧张素（Ang）II的合成，直接增加生产的纤维化细胞因子转化生长因子（TGF）-β。用人重组肾素（HrRenin）或大鼠重组肾素（RrRenin）处理人或大鼠系膜细胞（MCs），观察其对TGF-β 1、纤溶酶原激活物激活物1（派-1）、纤维连接蛋白（FN）和胶原1 mRNA和蛋白的影响。使用siRNA实现大鼠MC肾素受体的阻断。HrRenin或RrRenin在显示生理学相关的剂量下诱导TGF-β 1的显著剂量和时间依赖性增加。这些效果并没有改变，通过添加一种抑制剂的肾素的酶的作用（RO 42-5892），血管紧张素II受体拮抗剂氯沙坦或血管紧张素转换酶抑制剂依那普利。RrRenin还以剂量依赖方式诱导派-1、FN和胶原1 mRNA以及PAI-1和FN蛋白的表达。TGF-β的中和抗体部分阻断了这些作用。上清液和细胞裂解物Ang I和Ang II水平极低。MC血管紧张素原mRNA在有和没有加入肾素的情况下均检测不到。用siRNA靶向大鼠肾素受体mRNA阻断TGF-β 1的诱导。我们的结论是，肾素上调MC TGF-β 1通过受体介导的机制，独立于血管紧张素II的产生或行动。肾素诱导的TGF-β 1的增加反过来刺激派-1、FN和胶原蛋白I的增加。因此，肾素可能有助于肾纤维化疾病，特别是当治疗性血管紧张素II阻断升高血浆肾素。
Recent evidence suggesting a strong interplay between components of the renin-angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-beta. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-beta 1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-beta 1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-beta partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-beta 1. We conclude that renin upregulates MC TGF-beta 1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-beta 1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin.