Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: RGC (Response Gene to Complement)-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. Depending on the cell type, physiological or pathological conditions, RGC-32 can stimulate cell growth through increased p34CDC2 kinase activity and Akt phosphorylation or suppress it via arrest in mitotic progression. Previous studies by our group have shown that RGC-32 is critical for murine Th17 cell differentiation in vitro and in vivo. Initially identified in rat oligodendrocytes in response to sublytic C5b-9 complex, RGC-32 is induced by TGFβ in fibroblasts and human proximal tubular epithelial cells (PTEC) and mediates TGFβ dependent profibrotic pathways that contribute to renal fibrosis. RGC-32 expression has been described in tubules of normal human kidneys and its upregulation was reported in tubules from patients with IgA nephropathy. The expression patterns and function of RGC-32 in lupus nephritis (LN) have not yet been investigated.
Methods: In situ expression and localization of RGC-32 was assessed by immunohistochemistry in kidney biopsies from 25 lupus patients with proliferative lupus nephritis and 11 patients with other nephropathies (IgA nephropathy, minimal change disease, ANCA-associated glomerulonephritis, nephrosclerosis, acute tubular necrosis). In vitro, the expression of RGC-32 in human PTEC cells was assessed by Flow cytometry, Western blot and RT-PCR in the presence or absence of cytokines with known nephritogenic potential such as IL-1, TNFα, IFNγ and TGFβ.
Results: Consistent with the staining distribution reported in normal kidneys, RGC-32 immunostaining was predominant in proximal and distal tubules and was detected in a focal or diffuse pattern. Tubular mean staining intensity was significantly higher in SLE than in non-SLE specimens (2.0±0.23 vs 1.30±0.49; p=0.04) and was noted both in areas of normal appearing as well as damaged tubules. RGC-32 expression was also detected in glomeruli and in inflammatory cells in the interstitium of LN biopsies and colocalized with CD4+ T cells and CD68+ macrophages, respectively. Staining intensity was significantly higher in glomeruli and interstitium of LN specimens compared to disease controls (2.4±1.4 vs.1.6±0.8 and 1.8± 0.9 vs. 0.96±0.4 respectively) and correlated with the activity (r=0.4), chronicity (r=0.5) and interstitial fibrosis scores (r=0.5). In vitro, RGC- 32 mRNA and protein expression was upregulated in PTEC by nephritogenic cytokines including IL-1 (7.8 fold), TNFα (5 fold), TGFβ (3.1 fold) and to a lesser extent by IFNγ (2.1 fold).
Conclusion: RGC-32 expression is increased in glomeruli and tubulointerstitium from patients with lupus nephritis. Upregulation of RGC-32 is mediated by proinflammatory cytokines and may play pathogenetic role in organ damage in SLE by promoting manifestations of progressive renal disease such as interstitial fibrosis.
To cite this abstract in AMA style:Yip J, Nguyen V, Tatomir A, Mekala A, Boodhou D, Rus H, Drachenberg C, Rus V. Increased Expression of Response Gene to Complement-32 in Kidney Biopsies from Patients with Lupus Nephritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/increased-expression-of-response-gene-to-complement-32-in-kidney-biopsies-from-patients-with-lupus-nephritis/. Accessed November 28, 2020.
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