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.

Panax ginseng total protein promotes proliferation and secretion of collagen in NIH/3T3 cells by activating extracellular signal-related kinase pathway

“…MAPK/ERK signaling is an important pathway that affects cell proliferation, and can be activated by growth factors such as TGF-β1 [26], [27], [28]. Because our data showed that GTP induced the expression of TGF-β1, we therefore examined the effect of GTP on ERK signaling pathway by Western blotting and immunofluorescence staining.…”

TWEAK/Fn14 Activation Participates in Ro52-Mediated Photosensitization in Cutaneous Lupus Erythematosus

“…It is known that TWEAK regulates junctional proteins in cells via canonical NF-κB pathway and ERK activation (30). Our results showed that the TWEAK-induced Ro52 expression in keratinocytes can be suppressed by NF-κB or PI3K/Akt inhibitor but enhanced by MAPK/ERK inhibitor, suggesting that the NF-κB and PI3K pathways participate in the TWEAK regulation of Ro52.…”

Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury

“…56,57 TWEAK promotes partial EMT in renal tubular cells. 58 TWEAK-induced EMT was TGF-β1-and EGFR-independent, 58 in contrast to other profibrotic factors, such as angiotensin II. The EMT process triggered by TWEAK involves the activation of the classic NF-κB pathway and the MAPK ERK1/ 2 and the integration of both signaling pathways to downmodulate the expression of the vitamin D receptor.…”

“…Pharmacologic modulation of NF-κB and ERK activation, as well as restoration of vitamin D-receptor levels, restricted TWEAK-mediated EMT. 58 TWEAK-induced TGF-β1 up-regulation via Rasdependent protein kinase G type 1 (PKG-1) downregulation resulted in extracellular matrix production by cultured mesangial cells and in the whole kidney in vivo. 59 TWEAK also induces H/N-Ras/ERK-mediated proliferation and NF-κB-mediated release of inflammatory mediators in cultured renal fibroblasts.…”