S1P1-selective agonist, SEW2871, ameliorates ischemic acute renal failure

Y. H H Lien, K. C. Yong, C. Cho, S. Igarashi, Li-Wen Lai

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

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 S1P1 receptor, and may play a role in reducing ischemic renal injury. We examined the protective effects of a newly identified S1P1-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-α (TNF-α), 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-α, 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-α, 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.

Original languageEnglish (US)
Pages (from-to)1601-1608
Number of pages8
JournalKidney International
Volume69
Issue number9
DOIs
StatePublished - May 2006

Fingerprint

Acute Kidney Injury
Reperfusion Injury
Kidney
P-Selectin
Intercellular Adhesion Molecule-1
Ischemia
Reperfusion
Lymphocytes
Fluorescent Antibody Technique
Endothelial Cells
Lysosphingolipid Receptors
Neoplasms
Sphingosine
E-Selectin
SEW2871
Reverse Transcriptase Polymerase Chain Reaction
Transcriptome
Real-Time Polymerase Chain Reaction
Signal Transduction
Creatinine

Keywords

  • EDG1
  • ICAM-1
  • Ischemic renal injury
  • Lymphocytopenia
  • S1P
  • TNF-α

ASJC Scopus subject areas

  • Nephrology

Cite this

S1P1-selective agonist, SEW2871, ameliorates ischemic acute renal failure. / Lien, Y. H H; Yong, K. C.; Cho, C.; Igarashi, S.; Lai, Li-Wen.

In: Kidney International, Vol. 69, No. 9, 05.2006, p. 1601-1608.

Research output: Contribution to journalArticle

Lien, Y. H H ; Yong, K. C. ; Cho, C. ; Igarashi, S. ; Lai, Li-Wen. / S1P1-selective agonist, SEW2871, ameliorates ischemic acute renal failure. In: Kidney International. 2006 ; Vol. 69, No. 9. pp. 1601-1608.
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abstract = "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 S1P1 receptor, and may play a role in reducing ischemic renal injury. We examined the protective effects of a newly identified S1P1-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-α (TNF-α), 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-α, 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-α, 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.",
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AB - 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 S1P1 receptor, and may play a role in reducing ischemic renal injury. We examined the protective effects of a newly identified S1P1-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-α (TNF-α), 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-α, 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-α, 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.

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