Sphingosine kinase 2 deficiency attenuates kidney fibrosis via IFN-γ

Abstract

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 Sphk1-/- mice exhibited more kidney fibrosis than Sphk2-/- mice. Furthermore, kidneysof FA-treatedWT and Sphk12/2mice hadgreaterimmune cell infiltration and expression offibrotic and inflammatory markers than kidneys of FA-treated Sphk2-/- mice. In contrast, kidneys of Sphk2-/- mice exhibited greater expression of Ifng and IFNγ-responsive genes (Cxcl9 and Cxcl10) than kidneys of WT or Sphk1-/- mice did at this time point. Splenic T cells from untreated Sphk2-/- mice were hyperproliferative and producedmoreIFNγ thandidthose ofWTor Sphk1-/-mice. IFNγ blocking antibody administered to Sphk2-/- mice or deletion of Ifng (Sphk2-/-Ifng-/- mice) blocked the protective effect of SphK2 deficiency in fibrosis. Moreover, adoptive transfer of Sphk2-/- (but not Sphk2-/-Ifng-/-) CD4 T cells into WT mice blocked FAinduced fibrosis. Finally, a selective SphK2 inhibitor blocked FA-induced kidney fibrosis inWTmice. These studies demonstrate that SphK2 inhibition may serve as a novel therapeutic approach for attenuating kidney fibrosis.