Renin-stimulated TGF-β1 expression is regulated by a mitogen-activated protein kinase in mesangial cells
Renin-stimulated TGF-β1 expression is regulated by a mitogen-activated protein kinase in mesangial cells
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DOI：
10.1038/sj.ki.5002243
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发表时间：
2007-07-01
影响因子：
19.6
通讯作者：
Border, W. A.
中科院分区：
文献类型：
--
作者：
Huang, Y.;Noble, N. A.;Border, W. A.
最近的证据表明，肾素本身可能是促纤维化的，独立于血管紧张素II;然而，肾素发挥直接作用的信号系统尚不清楚。我们测试的假设，肾素受体激活，反过来，激活细胞外信号调节激酶1和2（ERK 1/2）的丝裂原活化蛋白激酶系统在系膜细胞。重组大鼠肾素以剂量和时间依赖性方式诱导ERK 1/2的快速磷酸化和随后的细胞增殖。ERK 1/2激活肾素除了不改变血管紧张素转换酶抑制剂或血管紧张素受体阻断剂。ERK激酶抑制剂显著降低了肾素诱导的ERK 1/2磷酸化以及随后的转化生长因子-β 1（TGF-β 1）和纤溶酶原激活物抑制剂-1 mRNA表达的增加。一个小的抑制RNA，siRNA，对肾素受体完全阻断ERK 1/2激活大鼠肾素。我们的结论是，肾素诱导ERK 1/2激活通过受体介导的，血管紧张素II的非依赖性机制在系膜细胞。这种肾素激活途径触发细胞增殖沿着TGF-β 1和纤溶酶原激活物抑制剂-1基因表达。该系统可能在肾素的整体促纤维化作用中发挥重要作用。
Recent evidence indicates that renin itself might be profibrotic, independent of angiotensin II; however, the signaling system by which renin exerts a direct effect is not known. We tested the hypothesis that renin receptor activation, in turn, activates the extracellular-signal regulated kinase 1 and 2 (ERK1/2) of the mitogen-activated protein kinase system in mesangial cells. Recombinant rat renin induced a rapid phosphorylation of ERK1/2 and subsequent cell proliferation in a dose- and time-dependent manner. ERK1/2 activation by renin addition was not altered by angiotensin-converting enzyme inhibition or angiotensin receptor blockade. An ERK kinase inhibitor significantly reduced the renin-induced ERK1/2 phosphorylation and the subsequent increase in transforming growth factor-beta 1 (TGF-beta 1) and plasminogen activator inhibitor-1 mRNA expression. A small-inhibiting RNA, siRNA, against the renin receptor completely blocked ERK1/2 activation by rat renin. We conclude that renin induces ERK1/2 activation though a receptor-mediated, angiotensin II-independent mechanism in mesangial cells. This renin-activated pathway triggers cell proliferation along with TGF-beta 1 and plasminogen activator inhibitor-1 gene expression. This system may play an important role in the overall profibrotic actions of renin.