Angiotensin II Induces Epithelial-to-Mesenchymal Transition in Renal Epithelial Cells through Reactive Oxygen Species/Src/Caveolin-Mediated Activation of an Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase Signaling Pathway

ABSTRACTCells that lead collective invasion can have distinct traits and regulatory programs compared to the cells that follow them. Notably, a specific type of epithelial-to-mesenchymal transition (EMT) program we term a “trailblazer EMT” endows cells with the ability to lead collective invasion and promote the opportunistic invasion of intrinsically less invasive siblings. Here, we sought to define the regulatory programs that are responsible for inducing a trailblazer EMT in a genetically engineered mouse (GEM) model of breast cancer. Analysis of fresh tumor explants, cultured organoids and cell lines revealed that the trailblazer EMT was controlled by TGFβ pathway activity that induced a hybrid EMT state characterized by cells expressing E-cadherin and Vimentin. Notably, the trailblazer EMT was active in cells lacking keratin 14 expression and evidence of trailblazer EMT activation was detected in collectively invading cells in primary tumors. The trailblazer EMT program required expression of the transcription factor Fra1, which was regulated by the parallel autocrine activation of the epidermal growth factor receptor (EGFR) and extracellular signal regulated kinases (ERK) 1 and 2. Together, these results reveal that the activity of parallel TGFβ and EGFR pathways confers cells with the ability to lead collective invasion through the induction of a trailblazer EMT.

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Role of NADPH Oxidase-Mediated Reactive Oxygen Species in Podocyte Injury

BioMed Research International ◽

10.1155/2013/839761 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 47

Author(s):

Shan Chen ◽

Xian-Fang Meng ◽

Chun Zhang

Keyword(s):

Reactive Oxygen Species ◽

Nadph Oxidase ◽

Epithelial To Mesenchymal Transition ◽

Kidney Diseases ◽

Treatment Strategies ◽

Reactive Oxygen ◽

Glomerular Sclerosis ◽

Oxygen Species ◽

Podocyte Injury ◽

Mesenchymal Transition

Proteinuria is an independent risk factor for end-stage renal disease (ESRD) (Shankland, 2006). Recent studies highlighted the mechanisms of podocyte injury and implications for potential treatment strategies in proteinuric kidney diseases (Zhang et al., 2012). Reactive oxygen species (ROS) are cellular signals which are closely associated with the development and progression of glomerular sclerosis. NADPH oxidase is a district enzymatic source of cellular ROS production and prominently expressed in podocytes (Zhang et al., 2010). In the last decade, it has become evident that NADPH oxidase-derived ROS overproduction is a key trigger of podocyte injury, such as renin-angiotensin-aldosterone system activation (Whaley-Connell et al., 2006), epithelial-to-mesenchymal transition (Zhang et al., 2011), and inflammatory priming (Abais et al., 2013). This review focuses on the mechanism of NADPH oxidase-mediated ROS in podocyte injury under different pathophysiological conditions. In addition, we also reviewed the therapeutic perspectives of NADPH oxidase in kidney diseases related to podocyte injury.

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