Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-γ
Sphingosine Kinase 2 Deficiency Attenuates Kidney Fibrosis via IFN-γ
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DOI：
10.1681/asn.2016030306
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发表时间：
2017-04-01
影响因子：
13.6
通讯作者：
Okusa, Mark D.
中科院分区：
文献类型：
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作者：
Bajwa, Amandeep;Huang, Liping;Okusa, Mark D.
急性肾损伤后的不适应修复可导致进行性纤维化和肾功能下降。鞘氨醇1-磷酸在肾损伤和纤维化中具有多效性作用。我们研究了鞘氨醇激酶1和2 （SphK1和SphK2）在叶酸（FA）或单侧缺血再灌注损伤引起的肾纤维化中的作用，SphK1和SphK2磷酸化鞘氨醇生成鞘氨醇1-磷酸。AKI后14天马松三色染色、纤维化标记蛋白和mRNA表达分析显示野生型（WT）和Sphk1（-/-）小鼠比Sphk2小鼠表现出更多的肾纤维化。此外，fa处理的WT和Sphk1（-/-）小鼠的肾脏比fa处理的Sphk2（-/-）小鼠的肾脏有更多的免疫细胞浸润和纤维化和炎症标志物的表达。相比之下，在这个时间点，Sphk2（-/-）小鼠的肾脏比WT或Sphk1（-/-）小鼠的肾脏表现出更高的Ifng和ifn - γ应答基因（CxcI9和Cxcl10）的表达。未经处理的Sphk2（-/-）小鼠的脾T细胞增生，比WT或Sphk1（-/-）小鼠产生更多的ifn - γ。给予Sphk2（-/-）小鼠ifn - γ阻断抗体或删除Ifng(Sphk2（-/-) Ifng（-/-）小鼠）可阻断Sphk2缺乏对纤维化的保护作用。此外，将Sphk2(-/-)(而非Sphk2(-/-)Ifng(-/-)) CD4 T细胞过继转移到WT小鼠体内，可阻断FA诱导的纤维化。最后，选择性SphK2抑制剂阻断fa诱导的WT小鼠肾纤维化。这些研究表明，抑制SphK2可能作为一种新的治疗方法来减轻肾纤维化。
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 (CxcI9 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.