TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation

Sandra Rayego-Mateos, Jose Luis Morgado-Pascual, Ana Belen Sanz, Adrian Mario Ramos, Satoru Eguchi, Daniel Batlle, Janos Pato, Gyorgy Keri, Jesus Egido, Alberto Ortiz, Marta Ruiz-Ortega*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

TWEAK, a member of the TNF superfamily, binds to the Fn14 receptor, eliciting biological responses. EGFR signalling is involved in experimental renal injury. Our aim was to investigate the relationship between TWEAK and EGFR in the kidney. Systemic TWEAK administration into C57BL/6 mice increased renal EGFR phosphorylation, mainly in tubular epithelial cells. In vitro, in these cells TWEAK phosphorylated EGFR via Fn14 binding, ADAM17 activation and subsequent release of the EGFR ligands HB-EGF and TGFα. In vivo the EGFR kinase inhibitor Erlotinib inhibited TWEAK-induced renal EGFR activation and downstream signalling, including ERK activation, up-regulation of proinflammatory factors and inflammatory cell infiltration. Moreover, the ADAM17 inhibitor WTACE-2 also prevented those TWEAK-induced renal effects. In vitro TWEAK induction of proinflammatory factors was prevented by EGFR, ERK or ADAM17 inhibition. In contrast, EGFR transactivation did not modify TWEAK-mediated NF-κB activation. Our data suggest that TWEAK transactivates EGFR in the kidney, leading to modulation of downstream effects, including ERK activation and inflammation, and suggest that inhibition of EGFR signalling could be a novel therapeutic tool for renal inflammation.

Original languageEnglish (US)
Pages (from-to)480-494
Number of pages15
JournalJournal of Pathology
Volume231
Issue number4
DOIs
StatePublished - Dec 1 2013

Keywords

  • ADAM17
  • EGFR
  • TWEAK
  • inflammation
  • renal

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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