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Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-? #MMPMID27799486
Bajwa A; Huang L; Kurmaeva E; Ye H; Dondeti KR; Chroscicki P; Foley LS; Balogun ZA; Alexander KJ; Park H; Lynch KR; Rosin DL; Okusa MD
J Am Soc Nephrol 2017[Apr]; 28 (4): 1145-61 PMID27799486show ga
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-??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-? than did those of WT or Sphk1?/? mice. IFN-? 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.