title: TNF-related weak inducer of apoptosis (TWEAK) regulates junctional proteins in tubular epithelial cells via canonical NF-κB pathway and ERK activation.
abstract: The tubular epithelium may be intrinsically involved in promoting kidney injury by junctional instability, epithelial-mesenchymal transition (EMT) and extracellular matrix remodelling. In this work, we investigated whether the pleiotropic and proinflammatory cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), could be able to disturb junctional protein expression and to induce EMT of tubular cells. In cultured murine proximal tubular cells TWEAK induced phenotypic changes that were accompanied by F-actin redistribution, loss of epithelial adherent (E-cadherin, Cadherin-16, β-catenin) and tight junction (ZO-1) proteins, and re-expression of the mesenchymal protein Vimentin. The transcriptional repressors Snail and HNF1β were also modulated by TWEAK. In a murine model of obstructive renal pathology, TWEAK expression correlated with the appearance of the mesenchymal marker αSMA in kidney tubular cells. Mechanistically, the epithelial changes induced by TWEAK, including loss of epithelial integrity and EMT, via Fn14 were TGF-β1 independent, but mediated by several intracellular signaling systems, including the canonical NF-κB, ERK activation and the vitamin D receptor modulation. These results highlight potential contributions of TWEAK-induced inflammatory mechanisms that could unveil new pathogenic effects of TWEAK starting tubulointerstitial damage and fibrosis.
authors.affiliation: Laboratory of Nephrology and Vascular Pathology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Berzal
authors.forename: Cristian
authors.initials: C
authors.lastname: González-Guerrero
authors.forename: Sandra
authors.initials: S
authors.lastname: Rayego-Mateos
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Ucero
authors.forename: Carlos
authors.initials: C
authors.lastname: Ocaña-Salceda
authors.forename: Jesús
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
authors.forename: Adrián M
authors.initials: AM
authors.lastname: Ramos
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000074049:Cytokine TWEAK; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000378:metabolism; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015820:Cadherins; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D018167:Receptors, Calcitriol; C109743:TNFSF12 protein, human; D062725:Tight Junction Proteins; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D048049:Extracellular Signal-Regulated MAP Kinases