Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis <i>via</i> IFN-<i>γ</i>.

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 <i>Sphk1^-/-</i> mice exhibited more kidney fibrosis than <i>Sphk2^-/-</i> mice. Furthermore, kidneys of FA-treated WT and <i>Sphk1^-/-</i> mice had greater immune cell infiltration and expression of fibrotic and inflammatory markers than kidneys of FA-treated <i>Sphk2^-/-</i> mice. In contrast, kidneys of <i>Sphk2^-/-</i> mice exhibited greater expression of <i>Ifng</i> and IFN-<i>γ</i>-responsive genes (<i>Cxcl9</i> and <i>Cxcl10</i>) than kidneys of WT or <i>Sphk1^-/-</i> mice did at this time point. Splenic T cells from untreated <i>Sphk2^-/-</i> mice were hyperproliferative and produced more IFN-<i>γ</i> than did those of WT or <i>Sphk1^-/-</i> mice. IFN-<i>γ</i> blocking antibody administered to <i>Sphk2^-/-</i> mice or deletion of <i>Ifng</i> (<i>Sphk2^-/-Ifng^-/-</i> mice) blocked the protective effect of SphK2 deficiency in fibrosis. Moreover, adoptive transfer of <i>Sphk2^-/-</i> (but not <i>Sphk2^-/-Ifng^-/-</i> ) 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.