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
- 1 March 2012
- journal article
- research article
- Published by Taylor & Francis in Molecular and Cellular Biology
- Vol. 32 (5), 981-991
- https://doi.org/10.1128/mcb.06410-11
Abstract
Chronic activation of the renin-angiotensin system plays a deleterious role in progressive kidney damage, and the renal proximal tubule is known to play an important role in tubulointerstitial fibrosis; however, the underlying molecular mechanism is unclear. Here we report that in the proximal tubule-like LLCPKcl4 cells expressing angiotensin II (Ang II) type 1 receptor, Ang II induced changes in cell morphology and expression of epithelial-to-mesenchymal transition (EMT) markers, which were inhibited by the miotogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK)-activating kinase (MEK) inhibitor PD98059 or the Src kinase inhibitor PP2. Ang II-stimulated phosphorylation of caveolin-1 (Cav) at Y14 and epidermal growth factor receptor (EGFR) at Y845 and induced association of these phosphoproteins in caveolin-enriched lipid rafts, thereby leading to prolonged EGFR-ERK signaling that was inhibited by Nox4 small interfering RNA (siRNA) and Src siRNA. Two different antioxidants not only inhibited phosphorylation of Src at Y416 but also blocked the EGFR-ERK signaling. Moreover, erlotinib (the EGFR tyrosine kinase inhibitor), EGFR siRNA, and Cav siRNA all inhibited both prolonged EGFR-ERK signaling and phenotypic changes induced by Ang II. Thus, this report provides the first evidence that reactive oxygen species (ROS)/Src-dependent activation of persistent Cav-EGFR-ERK signaling mediates renal tubular cell dedifferentiation and identifies a novel molecular mechanism that may be involved in progressive renal injury caused by chronic exposure to Ang IIThis publication has 45 references indexed in Scilit:
- (Pro)renin promotes fibrosis gene expression in HEK cells through a Nox4-dependent mechanismAmerican Journal of Physiology-Renal Physiology, 2011
- Lipid Rafts and Caveolin-1 Coordinate Interleukin-1β (IL-1β)-dependent Activation of NFκB by Controlling Endocytosis of Nox2 and IL-1β Receptor 1 from the Plasma MembraneJournal of Biological Chemistry, 2009
- Mitogenic Activity and Signaling Mechanism of 2-(14,15- Epoxyeicosatrienoyl)Glycerol, a Novel Cytochrome P450 Arachidonate MetaboliteMolecular and Cellular Biology, 2007
- Get Off My Back! Rapid Receptor Internalization through Circular Dorsal RufflesCancer Research, 2006
- Role of EGF Receptor Activation in Angiotensin II–Induced Renal Epithelial Cell HypertrophyJournal of the American Society of Nephrology, 2006
- A central role of EGF receptor transactivation in angiotensin II -induced cardiac hypertrophyTrends in Pharmacological Sciences, 2003
- Dominant negative c-Src inhibits angiotensin II induced activation of NHE3 in OKP cellsKidney International, 1998
- A detergent-free method for purifying caveolae membrane from tissue culture cells.Proceedings of the National Academy of Sciences, 1995
- Caveolin, a protein component of caveolae membrane coatsCell, 1992
- Angiotensin II binding sites in individual segments of the rat nephron.JCI Insight, 1986