Background/Purpose: Response Gene to Complement (RGC)-32 is a cell cycle regulator widely expressed in normal tissues including brain, kidney, spleen, thymus, multiple tumors and in a variety of cell lines. RGC-32 is localized in the cytoplasm and translocates to the nucleus upon upregulation by complement activation, growth factors and cytokines. RGC-32 is induced by TGF-β in fibroblasts, astrocytes and human renal proximal tubular cells and mediates TGF-β dependent profibrotic pathways. In immune cells, RGC-32 is upregulated preferentially in murine and human Th17 cells and promotes their differentiation in vitro and in vivo. Increased expression of IL-17 in kidneys of SLE patients and lupus prone mice is critical for the development of LN. We have previously shown that RGC-32 expression is increased in T cells from SLE patients and in tubules and glomerular infiltrating cells in kidney biopsies of patients with LN. To directly assess whether RGC-32 plays a local role in LN downstream of antibody production, we used the anti-glomerular basement membrane Ab-induced GN (AIGN) model to compare parameters of disease severity in RGC-32 deficient and sufficient mice.

Methods: Wild type (WT) and RGC-32-/- mice were immunized with sheep IgG in Complete Freund’s Adjuvant followed by injection of sheep nephrotoxic serum. Mice were monitored for proteinuria and blood urea nitrogen. Kidney histopathology was scored from 0 to 3 based on cellularity, endocapillary and mesangial proliferation, crescent formation, necrosis, fibrosis, tubular casts and dilatation. RGC-32 and IL-17A mRNA expression in kidneys was determined by qRT-PCR. Circulating levels and kidney deposition of mouse anti-sheep IgG were quantitated by ELISA and IF, respectively. Splenic B and T cell responses were characterized by flow cytometry.

Results: RGC-32 mRNA was significantly upregulated in the kidneys of WT mice with AIGN compared to controls. RGC-32-/- mice displayed an attenuated nephrotoxic injury as demonstrated by significantly decreased proteinuria, a trend for decreased blood urea nitrogen and decreased histopathological glomerular scores. Tubulointerstitial damage did not differ between RGC-32 sufficient and deficient mice. Correlating with RGC-32 expression, IL-17A mRNA expression was upregulated by 3 fold in kidneys of WT mice with AIGN while it was downregulated by 5 fold in RGC-32-/- mice. RGC-32 deficiency did not interfere with the induction of AIGN as mouse anti-sheep IgG titers, percentage of splenic germinal center B cells, plasma cells, effector CD4+ T cells, Tregs, IL-17A and IFN-g secreting cells did not differ between RGC-32-/- and WT mice. Furthermore, kidney deposition of autologous antibodies was comparable between the two groups.

Conclusion: These results suggest that RGC-32 contributes to the pathogenesis of immune complex mediated GN by promoting local IL-17A production and subsequently the development of end-organ damage. These data support further efforts to examine the mechanisms by which RGC-32 modulates local IL-17 expression and enhances kidney damage and suggest that RGC-32 is a potential novel therapeutic target in the treatment of LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/response-gene-to-complement-32-promotes-kidney-damage-in-immune-complex-mediated-glomerulonephritis/