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 language | English (US) |
|---|---|
| Pages (from-to) | 1601-1608 |
| Number of pages | 8 |
| Journal | Kidney International |
| Volume | 69 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 2006 |
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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 journal › Article
}
TY - JOUR
T1 - S1P1-selective agonist, SEW2871, ameliorates ischemic acute renal failure
AU - Lien, Y. H H
AU - Yong, K. C.
AU - Cho, C.
AU - Igarashi, S.
AU - Lai, Li-Wen
PY - 2006/5
Y1 - 2006/5
N2 - 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.
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.
KW - EDG1
KW - ICAM-1
KW - Ischemic renal injury
KW - Lymphocytopenia
KW - S1P
KW - TNF-α
UR - http://www.scopus.com/inward/record.url?scp=33646525690&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646525690&partnerID=8YFLogxK
U2 - 10.1038/sj.ki.5000360
DO - 10.1038/sj.ki.5000360
M3 - Article
C2 - 16572108
AN - SCOPUS:33646525690
VL - 69
SP - 1601
EP - 1608
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 9
ER -