S1P(1)-selective agonist, SEW2871, ameliorates ischemic acute renal failure.
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 transcriptase-polymerase 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 (P<0.01) and a significant reduction in tubular necrosis scores (I/R only: 4.3+/-0.2 vs I/R+SEW2871: 2.5+/-0.4, P<0.05) 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 P<0.01). The mRNA abundance of tumor necrotic factor-alpha (TNF-alpha), 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 P<0.05 vs sham). SEW2871 treatment partially reversed the upregulation of TNF-alpha, P-selectin, and ICAM-1 (47, 59, 54%, respectively, vs I/R control: 100%, all P<0.05). The reduction in protein expression of TNF-alpha, 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.
Section of Nephrology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona, USA. lien@u.arizona.edu
Y-Hh
YH
Lien
K-C
KC
Yong
C
C
Cho
S
S
Igarashi
L-W
LW
Lai
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013876:Thiophenes / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D015815:Cell Adhesion Molecules; D010069:Oxadiazoles; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha