Inhibition of Hyaluronan Synthesis or Hyaluronan-CD44 Interaction Attenuates Kidney Inflammation and Fibrosis in NZB/W F1 Mice

Background: Lupus nephritis (LN) is characterized by immune-mediated kidney injury, and it is an important cause of acute kidney injury and chronic kidney disease. Hyaluronan (HA) is a non-sulfated glycosaminoglycan implicated in tissue inflammation and fibrosis through binding to its cell surface receptor, CD44. We previously demonstrated that in patients with LN the circulating HA level correlated with the severity of chronic kidney damage as demonstrated in kidney biopsies. This study investigated the effect of 4-methylumbelliferone (4-MU), a specific inhibitor of HA synthesis, and anti-CD44 antibody, on disease manifestations and kidney fibrosis in an animal LN model of NZB/W F1 mice. Methods: HA expression was investigated in female NZB/W F1 mice showing proteinuria. In the first study, mice were randomized to receive either vehicle (Arabic Gum) or 4-MU in Arabic Gum for 12 weeks. In the second study, mice were randomized to receive either anti-CD44 antibody or Control IgG for 4 weeks and parameters related to kidney inflammation and fibrosis were assessed in both studies. Results: As disease progressed, mice treated with Arabic Gum or Control IgG showed glomerulosclerosis and neighboring glomerular hypertrophy, tubular dilation with flattening of epithelial cells, tubular protein casts and periglomerular and tubulo-interstitial mononuclear cell infiltration that included CD3+ and CD4+ T cells, CD19+ B cells and macrophages. Also, HA expression increased in the interstitium and periglomerular area, accompanied by increased CD44, TGF-β1, IL-1β, MCP-1, α-smooth muscle actin, fibronectin, collagen, VCAM-1, and NGAL expression. Treatment of mice with either 4-MU or anti-CD44 antibody preserved normal kidney histological structure, which was associated with reduced expression of mediators of tubulo-interstitial fibrosis and mononuclear inflammatory cell infiltration. Conclusion: The findings suggest that HA plays a key role in the pathogenesis of inflammation and fibrosis in LN, and suppression of HA synthesis or its interaction with CD44 may have therapeutic implications. Funding: Government Support – Non-U.S.