Novel interactions between TGF-β1 actions and the 12/15-lipoxygenase pathway in mesangial cells
Novel interactions between TGF-β1 actions and the 12/15-lipoxygenase pathway in mesangial cells
复制标题
DOI：
10.1681/asn.2004070568
复制
发表时间：
2005-02-01
影响因子：
13.6
通讯作者：
Natarajan, R
中科院分区：
文献类型：
--
作者：
Kim, YS;Xu, ZG;Natarajan, R
糖尿病肾病（DN）的特征是系膜细胞（MC）肥大和肾小球细胞外基质（ECM）进行性积累。最近有报道称，12/15-脂氧合酶 (12/15-LO) 表达在高葡萄糖 (HG) 刺激的 MC 和实验性 DN 中增加。 12-LO 产品还可以直接诱导 MC 肥大和 ECM 表达并介导生长因子效应，从而暗示 DN 中的 12/15-LO 途径。由于 TGF-β 是 DN 发病机制中的主要参与者，因此评估了 MC 中 TGF-β 和 12/15-LO 途径之间是否存在相互作用。用TGF-β处理大鼠MC (RMC)显着增加了12/15-LO产物12(S)-羟基二十碳四烯酸[12(S)-HETE]的水平以及12/15-LO mRNA和蛋白质表达。 RMC 中 HG 诱导的 TGF-β mRNA 表达受到针对敲除大鼠 12/15-LO 的特定核酶和 siRNA 的抑制。有趣的是，用 12(S)-HETE 直接处理 RMC 会增加 TGF-β mRNA 和蛋白质水平，以及 TGF-β 特异性靶转录因子 p-Smad2/3。 12(S)-HETE 还增加了最小 TGF-β 启动子的转录。此外，与对照小鼠相比，12/15-LO 敲除小鼠的 MC 中 TGF-β 表达和 p-Smad2/3 水平较低。相反，相对于模拟转染的细胞，稳定过表达 12/15-LO 的小鼠 MC 具有更高的 TGF-β mRNA 和核 p-Smad2/3。 12/15-LO 和 TGF-β 可以通过 p38 丝裂原激活蛋白激酶信号传导途径发出功能性信号并增加 ECM 表达。这些结果首次表明 12/15-LO 和 TGF-β 途径可以相互干扰并激活。这些新颖的相互作用可能会放大导致 DN 的信号转导级联和分子事件。
Diabetic nephropathy (DN) is characterized by mesangial cell (MC) hypertrophy and progressive accumulation of glomerular extracellular matrix (ECM). It was reported recently that 12/15-lipoxygenase (12/15-LO) expression is increased in high-glucose (HG)-stimulated MC and in experimental DN. 12-LO products could also directly induce MC hypertrophy and ECM expression and mediate growth factor effects, thus implicating the 12/15-LO pathway in DN. Because TGF-beta is a major player in the pathogenesis of DN, whether there is an interplay between the TGF-beta and 12/15-LO pathways in MC was evaluated. Treatment of rat MC (RMC) with TGF-beta significantly increased levels of the 12/15-LO product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] and also 12/15-LO mRNA and protein expression. HG-induced TGF-beta mRNA expression in RMC was inhibited by a specific ribozyme and siRNA targeted to knockdown rat 12/15-LO. It is interesting that direct treatment of RMC with 12(S)-HETE increased TGF-beta mRNA and protein levels, as well as p-Smad2/3, which are TGF-beta-specific target transcription factors. 12(S)-HETE also increased transcription from a minimal TGF-beta promoter. Furthermore, TGF-beta expression and p-Smad2/3 levels were lower in MC from 12/15-LO knockout mice relative to control mice. Reciprocally, mouse MC stably overexpressing 12/15-LO had greater TGF-beta mRNA and also nuclear p-Smad2/3 relative to mock-transfected cells. 12/15-LO and TGF-beta could functionally signal and increase ECM expression via the p38 mitogen-activated protein kinase signaling pathway. These results indicate for the first time that the 12/15-LO and TGF-beta pathways can cross-talk and activate each other. These novel interactions may amplify the signal transduction cascades and molecular events that lead to DN.