Induction of renal fibrotic genes by TGF-β1 requires EGFR activation, p53 and reactive oxygen species
Induction of renal fibrotic genes by TGF-β1 requires EGFR activation, p53 and reactive oxygen species
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DOI：
10.1016/j.cellsig.2013.07.007
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发表时间：
2013-11-01
影响因子：
4.8
通讯作者：
Higgins, Paul J.
中科院分区：
文献类型：
--
作者：
Samarakoon, Rohan;Dobberfuhl, Amy D.;Higgins, Paul J.
虽然转化生长因子-β（TGF-β 1）诱导的SMAD 2/3信号转导是慢性肾脏疾病进展中的关键事件，但非SMAD机制在纤维化基因变化的协调中的作用仍在很大程度上未被探索。TGF-β 1/SMAD 3通路在肾纤维化中的激活（输尿管结扎诱导）与表皮生长因子受体（Y845）相关（EGFR（Y845））和p53（Ser 15）磷酸化和诱导致病靶基因纤溶酶原激活物抑制剂-1（派-1）和结缔组织生长因子（CTGF）促使研究EGFR和肿瘤抑制因子p53在促纤维化信号传导中的机制参与。TGF-β 1、派-1、CTGF、p53和EGFR在梗阻的肾脏中共表达，主要定位于肾小管和间质室。事实上，TGF-β 1激活EGFR和p53以及SMAD 2/3。EGFR或p53的遗传缺陷或分别用AG 1478或Pifithrin-alpha的功能性阻断有效地抑制了PM-1和CTGF诱导和肾成纤维细胞的形态转化，如SMAD 3敲低或用SMAD 3抑制剂SIS 3预处理一样。由TGF-β 1启动的活性氧（ROS）依赖性机制对EGFRY 845和p53（ser 15）磷酸化和靶基因表达至关重要。NADPH氧化酶的p22（Phox）亚基也在纤维化肾脏中升高，其表达模式与p53和EGFR相似。单独的EGF刺激启动了C-末端SMAD 3磷酸化（需要TGF-β 1受体）和快速ERK 2激活，尽管延迟，这两者都是肾成纤维细胞中派-1和CTGF诱导所必需的。这些数据突出了SMAD 2/3、EGFR和p53通路之间的广泛串扰，这些通路对于TGF-β 1诱导的纤维化靶基因的表达至关重要。(C)2013 Elsevier Inc. All rights reserved.
While transforming growth factor-beta (TGF-beta 1)-induced SMAD2/3 signaling is a critical event in the progression of chronic kidney disease, the role of non-SMAD mechanisms in the orchestration of fibrotic gene changes remains largely unexplored. TGF-beta 1/SMAD3 pathway activation in renal fibrosis (induced by ureteral ligation) correlated with epidermal growth factor receptor(Y845) (EGFR(Y845)) and p53(Ser15) phosphorylation and induction of disease causative target genes plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) prompting an investigation of the mechanistic involvement of EGFR and tumor suppressor p53 in profibrotic signaling. TGF-beta 1, PAI-1, CTGF, p53 and EGFR were co-expressed in the obstructed kidney localizing predominantly to the tubular and interstitial compartments. Indeed, TGF-beta 1 activated EGFR and p53 as well as SMAD2/3. Genetic deficiency of either EGFR or p53 or functional blockade with AG1478 or Pifithrin-alpha, respectively, effectively inhibited PM-land CTGF induction and morphological transformation of renal fibroblasts as did SMAD3 knockdown or pretreatment with the SMAD3 inhibitor SIS3. Reactive oxygen species (ROS)-dependent mechanisms initiated by TGF-beta 1 were critical for EGFRY845 and p53(ser15) phosphorylation and target gene expression. The p22(Phox) subunit of NADPH oxidase was also elevated in the fibrotic kidney with an expression pattern similar to p53 and EGFR. EGF stimulation alone initiated, albeit delayed, c-terminal SMAD3 phosphorylation (that required the TGF-beta 1 receptor) and rapid ERK2 activation both of which are necessary for PAI-1 and CTGF induction in renal fibroblasts. These data highlight the extensive cross-talk among SMAD2/3, EGFR and p53 pathways essential for expression of TGF-beta 1-induced fibrotic target genes. (C) 2013 Elsevier Inc. All rights reserved.