ANGIOTENSIN-II STIMULATES EXTRACELLULAR-MATRIX PROTEIN-SYNTHESIS THROUGH INDUCTION OF TRANSFORMING GROWTH-FACTOR-BETA EXPRESSION IN RAT GLOMERULAR MESANGIAL CELLS
ANGIOTENSIN-II STIMULATES EXTRACELLULAR-MATRIX PROTEIN-SYNTHESIS THROUGH INDUCTION OF TRANSFORMING GROWTH-FACTOR-BETA EXPRESSION IN RAT GLOMERULAR MESANGIAL CELLS
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DOI：
10.1172/jci117251
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发表时间：
1994-06-01
影响因子：
15.9
通讯作者：
NOBLE, NA
中科院分区：
文献类型：
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作者：
KAGAMI, S;BORDER, WA;NOBLE, NA
血管紧张素 II (Ang II) 与进行性肾小球硬化症的发展有关，但这种作用的确切机制仍不清楚。在实验模型中，我们之前已经证明，TGF-β通过刺激细胞外基质蛋白合成、增加基质蛋白受体、改变蛋白酶/蛋白酶抑制剂平衡，从而抑制基质降解，在肾小球硬化中发挥关键作用。我们假设 Ang II 通过诱导 TGF-β 促进肾小球硬化。 Ang II 处理培养的大鼠肾小球系膜细胞，以时间和剂量依赖性方式在 mRNA 和蛋白质水平上增加 TGF-β 和基质成分双糖链蛋白聚糖、纤连蛋白和 I 型胶原。 Saralasin 是环 II 的竞争性抑制剂，可以阻止这种刺激。 Ang II 还促进潜在的 TGF-β 转化为生物活性形式。将系膜细胞与 Ang II 和 TGF-β 中和抗体共孵育，可阻断 Ang II 诱导的基质蛋白表达增加。正常大鼠体内连续给予 Ang II 7 天，导致肾小球 TGF-β 和 I 型胶原 mRNA 增加 70%。这些结果表明 Ang II 诱导系膜细胞合成基质蛋白，并表明这些作用是由 Ang II 诱导 TGF-β 表达介导的。这种机制很可能有助于体内肾小球硬化。
Angiotensin II (Ang II) has been implicated in the development of progressive glomerulosclerosis, but the precise mechanism of this effect remains unclear. In an experimental model, we have shown previously that TGF-beta plays a key role in glomerulosclerosis by stimulating extracellular matrix protein synthesis, increasing matrix protein receptors, and altering protease/protease-inhibitor balance, thereby inhibiting matrix degradation. We hypothesized that Ang II contributes to glomerulosclerosis through induction of TGF-beta. Ang II treatment of rat mesangial cells in culture increased TGF-beta and matrix components biglycan, fibronectin, and collagen type I at both the mRNA and protein levels in a time- and dose-dependent manner. Saralasin, a competitive inhibitor of ring II, prevented the stimulation. Ang II also promoted conversion of latent TGF-beta to the biologically active form. Coincubation of mesangial cells with Ang II and neutralizing antibody to TGF-beta blocked the Ang II-induced increases in matrix protein expression. Continuous in vivo administration of Ang II to normal rats for 7 d resulted in 70% increases in glomerular mRNA for both TGF-beta and collagen type I. These results indicate that Ang II induces mesangial cell synthesis of matrix proteins and show that these effects are mediated by Ang II induction of TGF-beta expression. This mechanism may well contribute to glomerulosclerosis in vivo.