The pathogenesis of renal ischemia/reperfusion (I/R) injury involves activating several signal transduction cascade systems in endothelial cells. Sphingosine 1-phospate (S1P) maintains endothelial cell integrity and inhibits lymphocyte egress via the specific S1P 1 receptor, and may play a role in reducing ischemic renal injury. We examined the protective effects of a newly identified S1P 1 -selective agonist, SEW2871, on mouse renal I/R injury. Kidneys were harvested 1-4 days after I/R injury for histopathology, immunofluorescence studies, and quantitative real-time reverse transcriptasepolymerase chain reaction analyses to assess the change in gene expression profiles of inflammation-associated cytokines and adhesion molecules. SEW2871 improved renal function with a 40% reduction in plasma creatinine levels (Po0.01) and a significant reduction in tubular necrosis scores (I/R only: 4.370.2 vs I/R þ SEW2871: 2.570.4, Po0.05) 24 h after ischemia. These changes were accompanied by 69% reduction in circulating lymphocytes, and 77 and 66% reduction in infiltrating neutrophils and macrophages in renal outer medulla, respectively (all Po0.01). The mRNA abundance of tumor necrotic factor-a (TNF-a), P-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) was markedly increased by I/R injury (3.5-, 4.1-, 3.5-, and 4.8-folds, respectively, all Po0.05 vs sham). SEW2871 treatment partially reversed the upregulation of TNF-a, P-selectin, and ICAM-1 (47, 59, 54%, respectively, vs I/R control: 100%, all Po0.05). The reduction in protein expression of TNF-a, P-selectin, and ICAM-1 was further confirmed with immunofluorescence studies. These results suggest that SEW2871 ameliorates renal I/R injury by inhibiting lymphocyte egress and reducing pro-inflammatory molecules. This new class of renoprotective agent shows promise as a novel approach in preventing/treating ischemic acute renal failure.

Seven weight-trained males performed both light resistance with partial occlusion (LRO: 30% 1 RM) and moderate resistance (MR: 70% 1 RM) to failure to ascertain whether blood protein carbonyls (PC) and glutathione status was altered compared to partial occlusion (PO) in a counterbalanced fashion. PO was identical in duration to the LRO session and all sessions were on separate days. PC did not differ for the three conditions at PRE (0.05 nM mg protein(-1)). PC significantly increased for PO and MR over time and was greater than the LRO treatment at POST (0.13 nM mg protein(-1)). The GSSG/TGSH ratio at PRE did not differ across treatments (8%) whereas the ratio at POST was significantly elevated for PO and MR treatments (17%). In contrast, no change occurred for the LRO session at any time. These results indicate that MR to failure and PO can significantly increase blood oxidative stress but LRO did not elicit oxidative stress.