title: TWEAK transactivation of the epidermal growth factor receptor mediates renal inflammation.
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.
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rayego-Mateos
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Morgado-Pascual
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Sanz
authors.forename: Adrian Mario
authors.initials: AM
authors.lastname: Ramos
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
authors.forename: Daniel
authors.initials: D
authors.lastname: Batlle
authors.forename: Janos
authors.initials: J
authors.lastname: Pato
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Keri
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology; D000072198:ADAM17 Protein; D000818:Animals; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D020868:Gene Silencing; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000074050:TWEAK Receptor; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000074049:Cytokine TWEAK; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D016328:NF-kappa B; D011799:Quinazolines; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D016211:Transforming Growth Factor alpha; D048069:Tumor Necrosis Factors; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: ADAM17; EGFR; TWEAK; inflammation; renal