EGFR signaling promotes TGFβ-dependent renal fibrosis

Jianchun Chen, Jiankang Chen, Kojiro Nagai, David Plieth, Mingqi Tan, Tang Cheng Lee, David W. Threadgill, Eric G. Neilson, Raymond C. Harris

Research output: Contribution to journalArticle

147 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)215-224
Number of pages10
JournalJournal of the American Society of Nephrology
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2012

ASJC Scopus subject areas

  • Nephrology

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    Chen, J., Chen, J., Nagai, K., Plieth, D., Tan, M., Lee, T. C., Threadgill, D. W., Neilson, E. G., & Harris, R. C. (2012). EGFR signaling promotes TGFβ-dependent renal fibrosis. Journal of the American Society of Nephrology, 23(2), 215-224. https://doi.org/10.1681/ASN.2011070645