EGFR signaling promotes TGFβ-dependent renal fibrosis.

Chen J, Chen JK, Nagai K, Plieth D, Tan M, Lee TC, Threadgill DW, Neilson EG, Harris RC
J Am Soc Nephrol. 2012 23 (2): 215-24

PMID: 22095949 · PMCID: PMC3269185 · DOI:10.1681/ASN.2011070645

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.

MeSH Terms (17)

Angiotensin II Animals ErbB Receptors Extracellular Signal-Regulated MAP Kinases Fibrosis Kidney LLC-PK1 Cells Male Mice Mice, Inbred BALB C Phosphorylation Reactive Oxygen Species Signal Transduction Smad2 Protein Smad3 Protein Swine Transforming Growth Factor beta

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