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1 Department of Medicine, University of Virginia, Charlottesville, VA, USA
2 Department of Chemistry, University of Virginia, Charlottesville, VA, USA
3 Department of Pharmacology, University of Virginia, Charlottesville, VA, USA; Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
4 Department of Medicine, University of Virginia, Charlottesville, VA, USA; Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: mdo7y{at}virginia.edu.
The mechanisms involved in renal ischemia-reperfusion injury (IRI) are complex and appear to involve the early participation of bone marrow derived cells. T lymphocytes participate in the pathogenesis of IRI. Sphingosine 1-phosphate (S1P) induces peripheral T cell depletion. Therefore we hypothesized that S1P1 receptor activation protects kidney from IRI. FTY720; a non receptor-selective sphingosine analog was given i.p. to C57BL/6 mice, and animals were subjected to ischemia for 32 min followed by reperfusion for 24 hours. Plasma creatinine, blood count, myeloperoxidase (MPO) activity and renal histology were determined. IRI led to marked increase in plasma creatinine, MPO activity, leukocyte infiltration and vascular permeability. FTY720 significantly decreased plasma creatinine in a dose response manner with a maximal reduction of ~73% and ~69% with doses of 240 µg/kg and 48 µg/kg, respectively. MPO, leukocyte infiltration, vascular permeability and peripheral blood lymphocyte counts were markedly decreased with FTY720 treatment. The protective effect of FTY720 was reversed with VPC44116, a selective S1P1 receptor antagonist. Furthermore, SEW2871; a selective S1P1 agonist, significantly decreased plasma creatinine in a dose response manner with a maximal reduction of ~70% with a dose of 10 mg/kg. Analysis of kidneys by light microscopy revealed minimal histologic signs of ischemic injury with FTY720 or SEW2871 treatment compared to vehicle group. Using RT-PCR, we found a time-dependent increase in the S1P1 mRNA expression following IRI that begins after 2h with the maximum expression at ~4h. We conclude that the protective effect of FTY720 is due primarily to activation of S1P1 receptors. The mechanism of protection is not known but may be related to peripheral lymphocyte depletion or direct effects on kidney cells expressing S1P1 receptor.
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