Increased cytokine expression of mesangial cells through altered glycosphingolipid catabolism in lupus nephritis

Abstract

Abstract Previously we demonstrated that glycosphingolipid (GSL) levels and neuraminidase (NEU) activity are altered in the kidneys and/or urine of lupus mice and human patients with nephritis compared to their non-nephritic counterparts and healthy controls. We also showed that sterol regulatory element-binding protein (SREBP)-1 expression is increased in the kidneys of nephritic lupus mice and altered GSL levels were observed in the glomerular region. Therefore, we hypothesized that NEU-mediated GSL catabolism is regulated by SREBP-1 and contributes to the production of cytokines by mesangial cells (MC) leading to renal inflammation in lupus nephritis. We now show co-localization of GSL lactosylceramide (LacCer) with MCs and increased expression of IL-6, IFNγ and other cytokines following addition of LacCer to cultured MCs. Primary MCs from pre-nephritic lupus mice stimulated with heat aggregated IgG (a mimic of immune complexes), LPS, or lupus serum showed elevated GSL levels, IL-6 production, MCP-1 expression and Neu1 expression. We now demonstrate that SREBP-1c expression is significantly upregulated in the kidney prior to overt nephritis compared to healthy controls. Over-expressing SREBP-1c in a MC line upregulated Neu1 promoter activity by two-fold, increased endogenous NEU1 expression and increased LacCer levels. Moreover, over-expressing either NEU1 or SREBP-1c significantly increased IL-6 production. Together these results suggest that MC activation leads to increased cytokine expression in part through NEU-mediated GSL catabolism regulated by SREBP-1c in lupus nephritis.