title: Sphingosine Kinase 2 Deficiency Attenuates Kidney FibrosisviaIFN-γ.
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) andSphk1-/-mice exhibited more kidney fibrosis thanSphk2-/-mice. Furthermore, kidneys of FA-treated WT andSphk1-/-mice had greater immune cell infiltration and expression of fibrotic and inflammatory markers than kidneys of FA-treatedSphk2-/-mice. In contrast, kidneys ofSphk2-/-mice exhibited greater expression ofIfngand IFN-γ-responsive genes (Cxcl9andCxcl10) than kidneys of WT orSphk1-/-mice did at this time point. Splenic T cells from untreatedSphk2-/-mice were hyperproliferative and produced more IFN-γthan did those of WT orSphk1-/-mice. IFN-γblocking antibody administered toSphk2-/-mice or deletion ofIfng(Sphk2-/-Ifng-/-mice) blocked the protective effect of SphK2 deficiency in fibrosis. Moreover, adoptive transfer ofSphk2-/-(but notSphk2-/-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.
authors: Division of Nephrology, ab9nh@virginia.edu dr5e@virginia.edu.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Amandeep
authors: A
authors: Bajwa
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Liping
authors: L
authors: Huang
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Elvira
authors: E
authors: Kurmaeva
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Hong
authors: H
authors: Ye
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Krishna R
authors: KR
authors: Dondeti
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Piotr
authors: P
authors: Chroscicki
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Leah S
authors: LS
authors: Foley
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Z Ayoade
authors: ZA
authors: Balogun
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Kyle J
authors: KJ
authors: Alexander
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Hojung
authors: H
authors: Park
authors: Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
authors: Kevin R
authors: KR
authors: Lynch
authors: Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and ab9nh@virginia.edu dr5e@virginia.edu.|Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
authors: Diane L
authors: DL
authors: Rosin
authors: Division of Nephrology.|Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
authors: Mark D
authors: MD
authors: Okusa
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D007371:Interferon-gamma / Q000502:physiology*; D007668:Kidney / Q000201:enzymology* / Q000473:pathology*; D007674:Kidney Diseases / Q000201:enzymology* / Q000517:prevention & control; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000172:deficiency*; D000099157:Sphingosine Kinase
chemical_list: D007371:Interferon-gamma; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase
keywords: T cells; folic acid; ischemia-reperfusion; renal fibrosis; sphingolipid