| First Author | Bajwa A | Year | 2017 |
| Journal | J Am Soc Nephrol | Volume | 28 |
| Issue | 4 | Pages | 1145-1161 |
| PubMed ID | 27799486 | Mgi Jnum | J:292972 |
| Mgi Id | MGI:6436171 | Doi | 10.1681/ASN.2016030306 |
| Citation | Bajwa A, et al. (2017) Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-gamma. J Am Soc Nephrol 28(4):1145-1161 |
| abstractText | 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, kidneys of FA-treated WT and Sphk1(-/-) mice had greater immune cell infiltration and expression of fibrotic and inflammatory markers than kidneys of FA-treated Sphk2(-/-) mice. In contrast, kidneys of Sphk2(-/-) mice exhibited greater expression of Ifng and IFN-gamma-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 produced more IFN-gamma than did those of WT or Sphk1(-/-) mice. IFN-gamma 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 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. |
