Anti-TWEAK Antibody Alleviates Renal Interstitial Fibrosis by Increasing PGC-1α Expression in Lupus Nephritis
Authors Xue L, Zhang Y, Xu J, Lu W, Wang Q, Fu J, Liu Z
Received 12 January 2021
Accepted for publication 11 March 2021
Published 26 March 2021 Volume 2021:14 Pages 1173—1184
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Ning Quan
Leixi Xue,1,* Yi Zhang,1,* Jiajun Xu,1 Wentian Lu,1 Qing Wang,1 Jinxiang Fu,2 Zhichun Liu1
1Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Zhichun Liu
Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Sanxiang Road No. 1055, Suzhou, Jiangsu, 215004, People’s Republic of China
Tel +86 13771994276
Email [email protected]
Department of Hematology, The Second Affiliated Hospital of Soochow University, Sanxiang Road No. 1055, Suzhou, Jiangsu, 215004, People’s Republic of China
Tel +86 13962525217
Email [email protected]
Purpose: Current studies on the mechanism of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis (LN) mainly focus on the inflammatory pathway. Herein, we aimed to determine whether TWEAK could promote the progression of renal interstitial fibrosis by regulating peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) expression and intervening in lipid metabolism in LN.
Materials and Methods: MRL/lpr mice, an animal model of lupus, were treated with the anti-TWEAK antibody or co-treated with adeno-associated virus-mediated PGC-1α short hairpin RNA (shRNA). In addition, human proximal tubular epithelial cells (HK2 cells) were treated with recombinant human TWEAK (rhTWEAK) or ammonium pyrrolidine dithiocarbamate (PDTC) in vitro.
Results: The renal contents of free fatty acids and triglycerides were higher in MRL/lpr mice than in MRL/MpJ mice; however, these contents were decreased by treatment with the anti-TWEAK antibody. Based on immunofluorescence staining, the expression of PGC-1α was markedly more in the renal tubules of MRL/MpJ mice than in the glomeruli. However, treatment with anti-TWEAK antibody increased the levels of PGC-1α and its downstream target genes, which were remarkably lower in MRL/lpr mice than in MRL/MpJ mice. Anti-TWEAK antibody effectively eased renal interstitial fibrosis, which manifested as a decrease in the deposition of collagen fibers and the inhibition of type I collagen and fibronectin expression. However, the therapeutic effects of the anti-TWEAK antibody were abolished by PGC-1α shRNA. Treatment with rhTWEAK decreased PGC-1α expression in both dose- and time-dependent manners in HK2 cells in vitro. PDTC, an inhibitor of IκBα phosphorylation, suppressed the decrease in the PGC-1α protein level induced by rhTWEAK treatment.
Conclusion: Our results suggest that TWEAK prevents renal tubular PGC-1α expression by promoting NF-κB activation, resulting in a deficiency in lipid metabolism and the progress of renal interstitial fibrosis. The upregulation of renal tubular PGC-1α expression to improve lipid metabolism is one of the mechanisms employed by the anti-TWEAK antibody to treat renal interstitial fibrosis.
Keywords: TWEAK, lupus nephritis, renal interstitial fibrosis, PGC-1α, lipid metabolism
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