title: Anti-dsDNA antibody induces soluble fibronectin secretion by proximal renal tubular epithelial cells and downstream increase of TGF-β1 and collagen synthesis.
abstract: The level of anti-dsDNA antibodies correlates with disease activity in lupus nephritis, but their role in pathogenic mechanisms remains to be defined. We investigated the effect of anti-dsDNA antibodies isolated from lupus nephritis patients on fibronectin synthesis and downstream fibrogenesis in proximal renal tubular epithelial cells (PTEC). Kidney biopsies were obtained from patients with active severe proliferative lupus nephritis. In vitro studies with cultured PTEC were performed to investigate the effect of human polyclonal IgG anti-dsDNA antibodies and mycophenolic acid (MPA). The role of IL-6, IL-8, MCP-1, TNF-α, TGF-β1, and MAPK and PKC signaling pathways on soluble and cell-associated fibronectin synthesis was investigated using neutralizing antibodies or specific inhibitors. The effect of exogenous endotoxin-free soluble fibronectin on downstream fibrotic processes was also examined. Fibronectin expression was markedly increased in the tubulo-interstitium of lupus nephritis renal biopsies and it co-localized with IgG deposition. Anti-dsDNA antibodies significantly increased both secreted and cell-associated fibronectin, through prior activation of ERK, p38 MAPK, JNK, PKC-α and PKC-βII. There was downstream induction of IL-6, IL-8, MCP-1, TNF-α and TGF-β1. MPA inhibited the induction of inflammatory and fibrotic processes by anti-dsDNA antibody. Exogenous soluble fibronectin induced TGF-β1 secretion and type I collagen synthesis in PTEC in a dose-dependent manner. Our data demonstrate that anti-dsDNA antibody contributes to tubulo-interstitial fibrosis in lupus nephritis through its action on PTEC. Anti-dsDNA antibody induces both cell-associated and soluble fibronectin secretion in PTEC, the former adds to extracellular matrix deposition while the latter amplifies the fibrotic process through induction of TGF-β1 and collagen type I. The pro-fibrotic effects of anti-dsDNA antibody are ameliorated by MPA.
authors: Department of Medicine, University of Hong Kong, Hong Kong. Electronic address: ssyyung@hku.hk.
authors: Susan
authors: S
authors: Yung
authors: Department of Medicine, University of Hong Kong, Hong Kong.
authors: Claudia Y C
authors: CY
authors: Ng
authors: Department of Medicine, University of Hong Kong, Hong Kong.
authors: Sau Kwan
authors: SK
authors: Ho
authors: Department of Medicine, University of Hong Kong, Hong Kong.
authors: Kwok Fan
authors: KF
authors: Cheung
authors: Department of Pathology, University of Hong Kong, Hong Kong.
authors: Kwok Wah
authors: KW
authors: Chan
authors: Department of Medicine, University of Hong Kong, Hong Kong.
authors: Qing
authors: Q
authors: Zhang
authors: Department of Medicine, University of Hong Kong, Hong Kong.
authors: Mel K M
authors: MK
authors: Chau
authors: Department of Medicine, University of Hong Kong, Hong Kong. Electronic address: dtmchan@hku.hk.
authors: Tak Mao
authors: TM
authors: Chan
mesh_terms: D000974:Antibodies, Antinuclear / Q000276:immunology*; D019138:Antibodies, Blocking / Q000276:immunology; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D004247:DNA / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000276:immunology*; D005355:Fibrosis; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000473:pathology*; D008181:Lupus Nephritis / Q000188:drug therapy / Q000276:immunology*; D009173:Mycophenolic Acid / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D000974:Antibodies, Antinuclear; D019138:Antibodies, Blocking; D005353:Fibronectins; D053773:Transforming Growth Factor beta1; D003094:Collagen; D004247:DNA; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D009173:Mycophenolic Acid
keywords: Anti-dsDNA antibodies; Fibronectin; Lupus nephritis; Mycophenolic acid; Proximal renal tubular epithelial cells