Fn14 Deficiency Ameliorates Anti-dsDNA IgG-Induced Glomerular Damage in SCID Mice.

Jiawen Wu,Li Wang,Xingyin Liu,Jie Yang,Yumin Xia,Xiaoyun Min,Ping Wang

doi:10.1155/2018/1256379

Abstract

Many studies have demonstrated that anti-dsDNA IgG is closely associated with lupus nephritis. Recently, it was found that activation of the fibroblast growth factor-inducible 14 (Fn14) signaling pathway damages glomerular filtration barrier in MRL/lpr lupus-prone mice. However, MRL/lpr mice have high titers of serum autoantibodies other than anti-dsDNA IgG. The aim of this study was to further explore the effect of Fn14 deficiency on anti-dsDNA IgG-induced glomerular damage in severe combined immunodeficiency (SCID) mice that have no endogenous IgG. Fn14 deficiency was generated in SCID mice. The murine hybridoma cells producing control IgG or anti-dsDNA IgG were intraperitoneally injected into mice. In two weeks, the urine, serum, and kidney tissue samples were harvested from mice at sacrifice. It showed that the injection of anti-dsDNA IgG, but not control IgG hybridoma cells, induced proteinuria and glomerular damage in SCID mice. Between the wild-type (WT) and knockout (KO) mice injected with anti-dsDNA IgG hybridoma cells, the latter showed a decrease in both proteinuria and glomerular IgG deposition. The histopathological changes, inflammatory cell infiltration, and proinflammatory cytokine production were also attenuated in the kidneys of the Fn14-KO mice upon anti-dsDNA IgG injection. Therefore, Fn14 deficiency effectively protects SCID mice from anti-dsDNA IgG-induced glomerular damage.

Highlights

Lupus nephritis (LN) is one of the most common complications occurring in the internal organs of patients with systemic lupus erythematosus (SLE)
Both immunohistochemistry and real-time PCR revealed that the anti-dsDNA IgG hybridoma cell-injected WT mice had higher factor-inducible 14 (Fn14) expression in glomeruli when compared with the KO mice (Figures 1(a) and 1(b))
Renal function was evaluated in these mice, revealing that the anti-dsDNA IgG hybridoma cell-injected WT mice had higher levels of urine albumin, serum creatinine, and Blood Urea Nitrogen (BUN) than the other mice, and these levels decreased significantly in the KO mice (Figures 1(d)–1(f))

Summary

Introduction

Lupus nephritis (LN) is one of the most common complications occurring in the internal organs of patients with systemic lupus erythematosus (SLE). Anti-dsDNA IgG binds to circulating nuclear antigens and forms immune complexes, which further deposit in the glomerular basement membrane. Anti-dsDNA IgG recognizes multiple renal self-antigens through cross-reaction, such as histone, heparan sulfate, laminin, collagen IV, alpha-actinin, and annexin II [3, 5,6,7,8,9]. Such cross-reaction between antidsDNA IgG and renal components leads to direct immune complex formation in local tissues or even IgG penetration into renal resident cells [6, 7]. Anti-dsDNA IgG induces fibronectin secretion of renal tubular epithelial cells and myofibroblast-like phenotype of mesangial cells [10, 11], which are early-stage events of renal fibrosis, a histopathologic feature associated with poor outcomes of LN

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