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TNF‐related weak inducer of apoptosis (TWEAK) regulates junctional proteins in tubular epithelial cells via canonical NF‐κB pathway and ERK activation
Author(s) -
Berzal Sergio,
GonzálezGuerrero Cristian,
RayegoMateos Sandra,
Ucero Álvaro,
OcañaSalceda Carlos,
Egido Jesús,
Ortiz Alberto,
RuizOrtega Marta,
Ramos Adrián M.
Publication year - 2015
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24905
Subject(s) - microbiology and biotechnology , proinflammatory cytokine , epithelial–mesenchymal transition , biology , mapk/erk pathway , signal transduction , cadherin , tumor necrosis factor alpha , chemistry , downregulation and upregulation , immunology , inflammation , cell , biochemistry , genetics , gene
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. J. Cell. Physiol. 230: 1580–1593, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company