Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Accelerates the Progression of Renal Fibrosis in Lupus Nephritis by Activating SMAD and p38 MAPK in TGF-β1 Signaling Pathway.

Zhiqin Liu,Zhichun Liu,Ji Hu,Leixi Xue,Ru Yang,Lin Bo,Jun Huang,Jian Wen

doi:10.1155/2016/8986451

Abstract

This study aim was to explore the effects of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis and its potential underlying mechanisms. MRL/lpr mice were used for in vivo experiments and human proximal tubular cells (HK2 cells) were used for in vitro experiments. Results showed that MRL/lpr mice treated with vehicle solution or LV-Control shRNA displayed significant proteinuria and severe renal histopathological changes. LV-TWEAK-shRNA treatment reversed these changes and decreased renal expressions of TWEAK, TGF-β1, p-p38 MAPK, p-Smad2, COL-1, and α-SMA proteins. In vitro, hTWEAK treatment upregulated the expressions of TGF-β1, p-p38 MAPK, p-SMAD2, α-SMA, and COL-1 proteins in HK2 cells and downregulated the expressions of E-cadherin protein, which were reversed by cotreatment with anti-TWEAK mAb or SB431542 treatment. These findings suggest that TWEAK may contribute to chronic renal changes and renal fibrosis by activating TGF-β1 signaling pathway, and phosphorylation of Smad2 and p38 MAPK proteins was also involved in this signaling pathway.

Highlights

The kidney is one of the most commonly affected organs in systemic lupus erythematosus (SLE); about half of the patients with SLE experience lupus nephritis (LN)
We have studied the role of Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in the activation of TGF-β1 through the canonical signaling pathways of TGF-β and p38 mitogenactivated protein kinase (MAPK) in vivo and in vitro
We have found that coculture with a concentration of 10 μg/mL anti-TWEAK mAb could functionally inhibit the role of TWEAK in cultured PBMC, so, in this study, we cocultured the hTWEAK-stimulated HK2 cells with 10 μg/mL anti-TWEAK monoclonal antibody, or with 10 μM SB431542 (TGF-β1 receptor kinase inhibitor, Sigma-Aldrich, Saint Louis, USA) or dimethyl sulfoxide alone

Summary

Introduction

The kidney is one of the most commonly affected organs in systemic lupus erythematosus (SLE); about half of the patients with SLE experience lupus nephritis (LN). The survival rate for patients with LN has improved to 88% over the last decade, approximately 10%–20% of these patients will develop end-stage renal disease (ESRD) [1] Fibrotic lesions such as sclerosed glomeruli, interstitial fibrosis, and fibrous vessels are strongly associated with poor renal outcomes in LN. Anti-Fn14 antibodies were found to reduce residual fibrosis in the acute phase of ischemia reperfusion in mice [17] These results suggest that TWEAK may contribute to chronic kidney injury and renal fibrosis in LN. Transforming growth factor-beta (TGF-β) signaling, enhanced by proinflammatory cytokines, is a central inducer of renal fibrosis [20]. The significance of TWEAK-TGF-β signaling pathway in the progression of renal fibrosis of lupus nephritis remains to be determined. We have studied the role of TWEAK in the activation of TGF-β1 through the canonical signaling pathways of TGF-β and p38 MAPK in vivo and in vitro

Materials and Methods

Results

Discussion