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

Abstract

INTRODUCTION AND AIMS: Rapamycin may have a role in the treatment of lupus nephritis due to its immunosuppressive and anti-proliferative properties. This study compared the effect of rapamycin and mycophenolate mofetil (MMF) on inflammatory and fibrotic mediators in a murine model of lupus nephritis. METHODS: Female NZB/W mice with established nephritis and proteinuria >3g/l were randomized to receive treatment with vehicle alone (control), MMF (100mg/kg/day), or rapamycin (3mg/kg/day) for 2, 6 and 12 weeks (n=6 for all time points in each group), and clinical parameters and renal histology assessed. RESULTS: Urine albumin-to-creatinine ratio and serum anti-DNA antibodies increased progressively in control mice. These abnormalities were ameliorated in both MMF and rapamycin treated groups (P<0.01 for both compared to control mice after 12 weeks). Both MMF and rapamycin treatment resulted in 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 and tubular atrophy compared to control mice. Both treatments also reduced glomerular IgG and C3 deposition, associated with reduced 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. CONCLUSIONS: Our data suggest that whilst both MMF and rapamycin can reduce clinical and serologic markers of disease in lupus nephritis, rapamycin may be less effective in suppressing tubulointerstitial expression of fibrosis markers compared with MMF.