Background/Purpose:

Renal mesangial cells, podocytes, and tubular cells express Fn14, the sole confirmed receptor for the tumor necrosis factor (TNF)-family member cytokine TWEAK (TNF-like weak inducer of apoptosis). The activation of the TWEAK/Fn14 pathway induces kidney resident cells to produce multiple proinflammatory mediators as well as promotes their proliferation or death. In the chronic graft-versus-host and nephrotoxic serum models of antibody-mediated renal disease, we had previously found that genetic deficiency of Fn14, or treatment with an anti-TWEAK monoclonal antibody, decreases kidney inflammation and proteinuria without affecting systemic autoantibody titers. These studies suggest that inhibition of TWEAK/Fn14 interactions might be efficacious in the treatment of immune-mediated renal diseases. The purpose of this study was to evaluate the effect of Fn14 deficiency in spontaneous murine lupus nephritis (LN).

Methods:

Fn14-knock out (KO) 129 mice were backcrossed for eight generations onto MRL-lpr/lpr (wild type, WT) mice to generate MRL/lpr, Fn14 KO mice. Age and sex-matched MRL/lpr Fn14 WT littermates and MRL/MpJ mice were used as control strains. The severity of renal damage was evaluated by measuring proteinuria and renal function, and immunohistochemical staining of kidney tissues. Immunofluorescent microscopy and transmission electron microscopy (TEM) were performed on frozen kidney sections. The systemic effect of Fn14 KO was assessed by determining the levels of autoantibodies in sera, assessing lymphadenopathy, and analyzing splenocytes numbers and subsets.  

Results:

We found that at 26 to 38 weeks of age, female MRL/lpr Fn14-WT mice had significantly higher levels of proteinuria, BUN, and serum creatinine as compared to female Fn14-KO mice. Moreover, MRL/lpr Fn14 KO mice had significantly improved renal histopathology, with less glomerular immune deposition, endocapillary hypercellularity, mesangial proliferation, and perivascular inflammation. TEM revealed less electron-dense deposits and fusion of podocyte foot processes along the glomerular basement membrane of Fn14 KO mice. Furthermore, scoring of renal injury markers revealed diminished expression of Ki-67 and TIM-1 in the Fn14-KO mice, while immunofluorescence staining revealed reduced glomerular nephrin expression in the Fn14-WT mice. While the lymphadenopathy score was significantly improved in Fn14-KO mice, there were no differences between the strains in both autoantibody titers (anti-dsDNA, chromatin, ribosomal P, or cardiolipin IgG) at any time point between 26-38 weeks, or in splenocyte subsets at 38 weeks of age, suggesting that TWEAK likely acts by modulating events locally in the kidney.

Conclusion:

Our results demonstrate that the inhibition of TWEAK signaling by genetically deleting the Fn14 receptor significantly improved renal damage in spontaneous LN in MRL-lpr mice, suggesting that the TWEAK/Fn14 axis may be a novel therapeutic target for LN.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-knock-out-of-tweak-receptorfn14-ameliorates-lupus-nephritis-in-mrllpr-mice/