Divergent roles of sphingosine kinases in kidney ischemia-reperfusion injury

Sphingosine-1-phosphate (S1P), produced by sphingosine kinase 1 (SphK1) or kinase 2 (SphK2), mediates biological effects through intracellular and/or extracellular mechanisms. Here we determined a role for these kinases in kidney injury of wild-type mice following ischemia-reperfusion. SphK1 but not SphK2 mRNA expression and activity increased in the kidney following injury relative to sham-operated animals. Although SphK1^-/- mice had no alteration in renal function following injury, mice with a disrupted SphK2 gene (SphK2 ^tr/tr) had histological damage and impaired function. The immune-modulating pro-drug, FTY720, an S1P agonist failed to provide protection in SphK2^tr/tr mice. Injured kidneys of these mice showed increased neutrophil infiltration and neutrophil chemokine expression along with a 3- to 5-fold increase in expression of the G-protein-coupled receptor S1P₃ compared to heterozygous SphK2^+/tr mice. Kidney function and reduced vascular permeability were preserved in S1P₃^-/- compared to S1P₃^+/- mice after ischemia-reperfusion injury, suggesting increased S1P₃ mRNA may play a role in the injury of SphK2^tr/tr mice. Our study suggests that constitutive expression of SphK2 may contribute to reduced ischemia-reperfusion injury of the kidney, and its absence may enhance injury due to increased neutrophil infiltration and S1P₃ activation. We also confirm that SphK2 is necessary to mediate the protective effects of FTY720.