Increased expression of Response Gene to Complement-32 in PBMC and kidneys of patients with lupus nephritis 2247376

Abstract

Abstract Introduction We have previously shown that response gene to complement-32 (RGC-32) promoted the Th17 and Th1 dependent proinflammatory and profibrotic responses in a murine model of immune complex mediated glomerulonephritis. The expression and function of RGC-32 in PBMC and kidney biopsies from patients with lupus nephritis (LN) have not yet been investigated. Methods RGC-32 expression was evaluated by RT-PCR, WB, flow cytometry and cDNA Array in PBMC from lupus patients and controls and in human proximal tubular epithelial cells (PTEC) and by immunohistochemistry in kidney biopsies from 25 patients with LN and 11 disease controls. Results RGC-32 mRNA expression was highest in CD3 cells followed by CD14 and CD19 cells and was increased in CD14 and CD19 cells from patients with vs those without renal disease. RGC-32 expression was induced by T cell stimulation under Th17 and Treg conditions and by serum from patients with high titer anti-dsDNA Ab. In kidneys, RGC-32 immunostaining was predominant in tubules and staining intensity was significantly higher in SLE than in non-SLE specimens. RGC-32 expression was also detected in glomeruli and in inflammatory cells in the interstitium, was significantly higher in LN specimens vs. controls and correlated with the activity (r = 0.4), chronicity (r = 0.5) and interstitial fibrosis scores (r = 0.5). RGC-32 colocalized with CD4+, CD68+ cells and C5b-9 deposition. In PTEC, RGC- 32 mRNA and protein expression was upregulated by IL-1, TNFα, TGFβ, IFNγ and sublytic C5b-9. TGFβ induced mRNA production of Collagen I and collagen III by PTEC was increased in RGC-32 transfected cells. Conclusion RGC-32 is upregulated in PBMC, glomeruli and tubulointerstitium of patients with LN. RGC-32 upregulation in PTEC is mediated by proinflammatory cytokines and complement activation and may play a role in organ damage by promoting manifestations of progressive renal disease such as interstitial fibrosis. Thus, RGC-32 is a potential therapeutic target in the treatment of LN. Funding Source N/A Topic Categories Immune Mechanisms of Human Disease (HUM)