Suppression of hyaluronan synthesis with 4-methylumbelliferone in NZB/W F1 mice is associated with reduced renal inflammation and renal function improvement

Abstract

BACKGROUND: We previously demonstrated that glomerular hyaluronan (HA) expression is increased in lupus nephritis, but its role in pathogenesis remains to be determined. This study investigated the effect of 4-methylumbelliferone, a specific inhibitor of HA synthesis, on disease manifestations in a lupus mouse model. METHODS: Female NZB/W F1 mice with established nephritis and proteinuria greater than 3g/l were randomized to receive treatment with sterile PBS, vehicle alone (1% Arabic Gum in PBS) or 4-methylumbelliferone in 1% Arabic Gum (MU, 3g/kg/day) for 2, 4, 8 and 12 weeks (n=6 for all time points for each group), after which the mice were sacrificed, blood collected and kidneys harvested for assessment of histology and expression of inflammatory mediators. Spot urine was obtained for the measurement of albumin-to-creatinine ratio. RESULTS: Serum HA levels increased in a time-dependent manner as disease progressed in PBS and vehicle treated mice. This was associated with increased periglomerular and tubulo-interstitial HA expression. MU treatment for 12 weeks reduced serum HA level by 30% and decreased renal HA expression to near normal levels. Urine albumin-to-creatinine ratio and serum levels of urea and creatinine increased in both PBS and vehicle treated mice with progressive disease, but were significantly decreased in mice after 12 weeks of MU treatment (P<0.05 for all, compared to both control groups). MU-treated mice also showed reduced glomerular deposition of IgG and C3, IL-6 and TNF-α expression, and glomerular infiltration by CD4+ T cells, CD19+ B cells and macrophages compared to controls. CONCLUSIONS: These results suggest that HA plays an important role in the pathogenesis of lupus nephritis and suppression of HA synthesis can ameliorate disease manifestations.