| Autor: |
Amandeep, Bajwa, Liping, Huang, Elvira, Kurmaeva, Hong, Ye, Krishna R, Dondeti, Piotr, Chroscicki, Leah S, Foley, Z Ayoade, Balogun, Kyle J, Alexander, Hojung, Park, Kevin R, Lynch, Diane L, Rosin, Mark D, Okusa |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Journal of the American Society of Nephrology : JASN. 28(4) |
| ISSN: |
1533-3450 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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