Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis IFN-.

Maladaptive repair after AKI may lead to progressive fibrosis and decline in kidney function. Sphingosine 1-phosphate has an important role in kidney injury and pleiotropic effects in fibrosis. We investigated the involvement of sphingosine kinase 1 and 2 (SphK1 and SphK2), which phosphorylate sphingosine to produce sphingosine 1-phosphate, in kidney fibrosis induced by folic acid (FA) or unilateral ischemia-reperfusion injury. Analysis of Masson trichrome staining and fibrotic marker protein and mRNA expression 14 days after AKI revealed that wild-type (WT) and mice exhibited more kidney fibrosis than mice. Furthermore, kidneys of FA-treated WT and mice had greater immune cell infiltration and expression of fibrotic and inflammatory markers than kidneys of FA-treated mice. In contrast, kidneys of mice exhibited greater expression of and IFN--responsive genes ( and ) than kidneys of WT or mice did at this time point. Splenic T cells from untreated mice were hyperproliferative and produced more IFN- than did those of WT or mice. IFN- blocking antibody administered to mice or deletion of ( mice) blocked the protective effect of SphK2 deficiency in fibrosis. Moreover, adoptive transfer of (but not ) CD4 T cells into WT mice blocked FA-induced fibrosis. Finally, a selective SphK2 inhibitor blocked FA-induced kidney fibrosis in WT mice. These studies demonstrate that SphK2 inhibition may serve as a novel therapeutic approach for attenuating kidney fibrosis.