title: EGFR signaling promotes TGFβ-dependent renal fibrosis.
abstract: The mechanisms by which angiotensin II (Ang II) promotes renal fibrosis remain incompletely understood. Ang II both stimulates TGFβ signaling and activates the EGF receptor (EGFR), but the relative contribution of these pathways to renal fibrogenesis is unknown. Using a murine model with EGFR-deficient proximal tubules, we demonstrate that upstream activation of EGFR-dependent ERK signaling is critical for mediating sustained TGFβ expression in renal fibrosis. Persistent activation of the Ang II receptor stimulated ROS-dependent phosphorylation of Src, leading to sustained EGFR-dependent signaling for TGFβ expression. Either genetic or pharmacologic inhibition of EGFR significantly decreased TGFβ-mediated fibrogenesis. We conclude that TGFβ-mediated tissue fibrosis relies on a persistent feed-forward mechanism of EGFR/ERK activation through an unexpected signaling pathway, highlighting EGFR as a potential therapeutic target for modulating tissue fibrogenesis.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Chen
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Chen
authors.forename: Kojiro
authors.initials: K
authors.lastname: Nagai
authors.forename: David
authors.initials: D
authors.lastname: Plieth
authors.forename: Mingqi
authors.initials: M
authors.lastname: Tan
authors.forename: Tang-Cheng
authors.initials: TC
authors.lastname: Lee
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Eric G
authors.initials: EG
authors.lastname: Neilson
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000032:analysis; D051900:Smad3 Protein / Q000032:analysis; D013552:Swine; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
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