Abstract
Glycosphingolipids (GSLs) hexosylceramides and lactosylceramides are elevated in lupus mice and human patients with nephritis. Whereas other renal diseases characterized by increased GSL levels are thought to be a result of upregulated GSL synthesis, our results suggest elevated hexosylceramides and lactosylceramides in lupus nephritis is a result of increased catabolism of ganglioside GM3 due to significantly increased neuraminidase (NEU) activity. Thus, we hypothesized GM3 would be decreased in lupus nephritis kidneys and blocking NEU activity would reduce GSLs and improve disease in lupus mice. Female MRL/lpr lupus mice were treated with water or the NEU inhibitor oseltamivir phosphate at the onset of proteinuria to block GSL catabolism. Age-matched (non-nephritic) female MRL/MpJ lupus mice served as controls. Renal GM3 levels were significantly higher in the nephritic MRL/lpr water-treated mice compared to non-nephritic MRL/MpJ mice, despite significantly increased renal NEU activity. Blocking GSL catabolism increased, rather than decreased, renal and urine GSL levels and disease was not significantly impacted. A pilot study treating MRL/lpr females with GlcCer synthase inhibitor Genz-667161 to block GSL synthesis resulted in a strong significant negative correlation between Genz-667161 dose and renal GSL hexosylceramide and GM3 levels. Splenomegaly was negatively correlated and serum IgG levels were marginally correlated with increasing Genz-667161 dose. These results suggest accumulation of renal GM3 may be due to dysregulation of one or more of the GSL ganglioside pathways and inhibiting GSL synthesis, but not catabolism, may be a therapeutic approach for treating lupus nephritis.
Highlights
GSLs are enriched in the kidney and GSL metabolism is altered in several kidney diseases, including lupus nephritis [6, 7, 10, 13]
We demonstrated that, despite increased NEU activity, renal GM3 levels were higher in kidneys of nephritic MRL/lpr mice compared to non-nephritic MRL/MpJ mice
We demonstrated SMs, Sphingosine-1 Phosphate (S1P), So, Dihydrosphingosine-1 Phosphate (DHS1P), and DHSo are elevated in the kidneys of nephritic MRL/lpr mice compared to the kidneys of non-nephritic MRL/MpJ mice
Summary
Systemic Lupus Erythematosus (SLE or lupus) is an autoimmune disease characterized by the development of autoantibodies, immune complex formation and deposition in target organs, PLOS ONE | https://doi.org/10.1371/journal.pone.0230499 March 18, 2020Targeting glycosphingolipid metabolism in lupus mice recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. We also acknowledge the support of the Medical University of South Carolina Multidisciplinary Clinical Research Center (now Core Centers for Clinical Research) (pilot funding awarded to TKN); the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313) and the Lipidomics Core in the SC Lipidomics and Pathobiology COBRE (P20 RR017677); and Virginia Commonwealth University Lipidomics/ Metabolomics Core, the NIH-NCI Cancer Center Support Grant P30 CA016059 to the Massey Cancer Center, as well as a shared resource grant (S10RR031535) from the National Institutes of Health. (Sanofi) Genzyme Corporation (Waltham, MA) provided the glucosylceramide synthase inhibitor Genz-667161, but had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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