Comparison of mycophenolate mofetil and rapamycin on inflammatory and fibrotic mediators in NZB/W mice with active nephritis

Abstract

Rapamycin might have a role in the treatment of lupus nephritis because of its immunosuppressive and anti-proliferative effect. This study compared the effect of rapamycin and mycophenolate mofetil (MMF) on inflammatory and fibrotic mediators in a murine lupus nephritis model. Female NZB/W mice with established nephritis and proteinuria >3g/L were randomized to receive treatment with vehicle alone (control), MMF (100mg/kg/d), or rapamycin (3mg/kg/d) for 2, 6 and 12 weeks (n=6 for all time points in each group), and clinical parameters and renal histology assessed. Albumin-to-creatinine ratio and circulating anti-DNA antibodies increased progressively in control mice, and these abnormalities were ameliorated in both MMF and rapamycin treated groups (P<0.01 for both compared to control mice after 12 weeks). Mice treated with MMF or rapamycin demonstrated reduced glomerular expansion (glomerular tuft area: 4252.15±324.15, 2645.76±564.21 and 2648.21±468.32μm2 for control, MMF and rapamycin respectively, P<0.01 for control vs MMF or rapamycin after 12 weeks treatment), and decreased interstitial fibrosis as well as tubular atrophy compared to control mice. Both MMF and rapamycin significantly reduced glomerular IgG and C3 deposition and this was associated with the abrogation of intra-glomerular expression of CD4, CD8, CD19 and MAC-1. Renal expression of IL-6, TGF-β1, fibronectin and collagen type I was reduced to near normal levels in MMF treated mice, whilst tubular expression of the aforementioned fibrotic markers was still significant in mice treated with rapamycin for 12 weeks. These results suggest that while both MMF and rapamycin ameliorate disease manifestations in lupus nephritis, rapamycin might be less effective in suppressing tubulointerstitial expression of fibrosis markers compared with MMF.