In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 4 ( 2017-4), p. 1145-1161
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, 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- γ –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- γ than did those of WT or Sphk1−/− mice. IFN- γ 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.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2016030306
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
2029124-3
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