Hyaluronan in the pathogenesis of lupus nephritis in NZB/W mice and the effect of 4-methylumbelliferone

Abstract

OBJECTIVES: Renal inflammation is a hallmark of lupus nephritis. Hyaluronan (HA) is a non-sulfated glycosaminoglycan ubiquitous in the extracellular environment of all cells. Tissue inflammation and fibrosis are associated with increased HA levels. Increased glomerular and tubular-interstitial HA expression has been shown in lupus nephritis, but its role in pathogenesis remains to be defined. Using 4-methylumbelliferone (MU), a specific inhibitor of HA synthesis, we examined the role of HA on renal histopathology and clinical manifestations in NZB/W mice with lupus nephritis. METHODS: Twenty-four female NZB/W mice with active nephritis denoted by persistent proteinuria >300mg/dl were divided into 4 groups and administered saline or MU (0.5, 1.0 or 5.0 mg/kg/day) by oral gavage for 12 weeks. They were then sacrificed and the urine, blood and kidneys analysed. RESULTS: MU significantly reduced serum HA levels in a dose-dependent manner compared to controls (p<0.05). This was associated with reductions in anti-dsDNA antibody titre (1316±718ng/ml vs 807±381ng/ml, control vs 5mg/kg/day MU, p<0.05), urine protein-to-creatinine ratio (23 vs 13 mg/mg creatinine for corresponding groups, p<0.05), and splenomegaly (0.16g vs 0.12 g for corresponding groups, p<0.05). Mice with active nephritis showed glomerular hypertrophy and increased intra-renal expression of CD4, CD8, CD19, CD23, CD45 and Mac-1. The intra-glomerular expression of HA and its receptor CD44, as well as that of IL-6 and MCP-1, was also increased. These changes were abrogated in mice treated with MU at 1 and 5 mg/kg/day. CONCLUSIONS: Our data suggest that HA participates in the pathogenesis of inflammation and histopathologic manifestations of renal injury in lupus nephritis, and thus may be a potential target for therapy.