Increased survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-phosphate receptor agonist.
Increased survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-phosphate receptor agonist.
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DOI：
10.1038/ki.2008.396
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发表时间：
2008-11
影响因子：
19.6
通讯作者：
Braun, Michael C.
中科院分区：
文献类型：
--
作者：
Wenderfer, Scott E.;Stepkowski, Stanislaw M.;Braun, Michael C.
Agonists of the type 1 sphingosine-1-phosphate receptor (S1P1) render lymphocytes unable to migrate along an S1P gradient, thereby causing sequestration in lymphoid organs. While the S1P agonist FTY720 prolongs the survival of organ allografts and blocks T-cell mediated autoimmune diseases in experimental models, it is a non-selective agonist of four out of five S1P receptors. A derivative compound, KRP-203, is a novel more selective agonist of the S1P1 receptor. In the present study, MRL/lpr mice were treated orally with KRP-203 or vehicle alone starting at 12 (prevention) or 16 (treatment) wks of age. Eighty percent of mice in the prevention group survived to 24 wks, compared to 50% of controls. There was less tubulointerstitial disease and 4- to 8- fold fewer infiltrating CD4+ and CD8+ T-cells (p<0.05). Survival to 24 wks was 100% in the treatment group (p=0.02), and these mice also had reduced proteinuria (p=0.02). As expected, both groups had 6-fold reductions in circulating lymphocytes (p=0.04). However, contrary to reports of shorter courses with S1P agonists, mice receiving 8–12 wks of KRP-203 had less adenopathy due primarily to 5- to 10-fold reductions in T-cells (p<0.05). Treatment of lymphocytes from MRL/lpr mice with KRP-203 ex vivo enhanced cell death via apoptosis. These data indicate that KRP-203 is an effective agent in the attenuation of kidney injury in MRL/lpr mice, mediated in part by reductions in T-cell infiltrates.
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