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MUSC Poster Presentations

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Pharmacologic Sphingosine Kinase Inhibition with ABC294640 Prevents Proteinuria and Improves Survival
Pharmacologic Sphingosine Kinase Inhibition with ABC294640 Prevents Proteinuria and Improves Survival In the MRL/lpr Murine Model of Lupus Poster presentation. Abstract: Purpose. Sphingosine kinases (SKs) phosphorylate sphingosine to create sphingosine 1 phosphate (S1P), which is involved in cell survival, proliferation, motility, and inflammation via intracellular signaling through release of Ca2+ stores, activation of NF??B, and extracellular interactions with G protein-coupled receptors (S1P receptors 1-5). Inhibitors of SK1 have been used successfully to treat experimental murine inflammatory bowel disease, diabetic retinopathy, and rheumatoid arthritis. SK1 is expressed in mesangial cells and plays a role in mesangial cell migration. The role of SKs in promoting inflammation in lupus is unknown. We hypothesized that ABC294640 (ABC), an orally available SK inhibitor, would reduce markers of glomerular pathology in the MRL/MpJTnfrsf6lpr/ J (MRL/lpr) murine model of lupus. Methods. Eleven MRL/lpr mice were treated with either polyethylene glycol (PEG, n=5) or ABC in PEG (50 mg/kg/day, n=6) from 10 (before onset of disease) to 20 weeks of age (significant albuminuria present). Urine was collected every other week and analyzed for albumin. Moribund mice were sacrificed, and all measures were carried forward. At 20 weeks, kidney and total weights were determined. Renal, skin, and joint tissue were harvested for histopathological scoring, while renal tissue was stained for IgG/C3 deposition and examined by electron microscopy. Serum anti-double stranded DNA antibody levels were determined at 20 weeks. Urine thromboxane levels were determined at 16 weeks. Spleen cell subsets were determine by flow cytometry. Differences between groups were determined by t-test or Wilcoxon rank sum analysis. Results were reported as averages standard error. Results. Survival was greater in ABC-treated mice than controls (100 vs. 40% at 20 weeks). By 18 and 20 weeks, proteinuria was lower in ABC-treated mice than control mice (106 vs. 3818 and 191 vs. 6021). Kidney/total body weights were significantly lower in ABC-treated mice than controls (1.50.1 vs. 2.20.1 mg/g, p=0.001). There was a trend towards lower renal thromboxane production in treated mice. Renal and cutaneous pathologic scores were lower in treated mice. Neither anti-double stranded DNA antibody production nor basement membrane and mesangial IgG/C3 staining were different between groups. Spleen marginal zone B cells were greater in treated mice. Conclusions. ABC294640 treatment improves survival, possibly due to reduced renal failure and vasculitis. ABC294640 treatment reduces often clinically refractory necrotic/crescentic glomerular lesions associated with reduced renal function in humans, making SK an attractive target for investigation as adjunctive therapy ABC294640 treatment reduces podocyte flattening associated with nephrotic range proteinuria in humans, making SK a possible target for investigation as adjunctive therapy in membranous nephritis with nephrotic range proteinuria. Improvements in outcomes are independent of changes in production and deposition of nephritic autoantibodies. We hypothesize that inhibition of SK may reduce homing of inflammatory cells and activation of resident and inflammatory cells to produce inflammatory mediators such as thromboxane.