Bajwa Amandeep, Huang Liping, Kurmaeva Elvira, Ye Hong, Dondeti Krishna R, Chroscicki Piotr, Foley Leah S, Balogun Z Ayoade, Alexander Kyle J, Park Hojung, Lynch Kevin R, Rosin Diane L, Okusa Mark D
Division of Nephrology,
Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and.
J Am Soc Nephrol. 2017 Apr;28(4):1145-1161. doi: 10.1681/ASN.2016030306. Epub 2016 Oct 31.
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 mice exhibited more kidney fibrosis than mice. Furthermore, kidneys of FA-treated WT and mice had greater immune cell infiltration and expression of fibrotic and inflammatory markers than kidneys of FA-treated mice. In contrast, kidneys of mice exhibited greater expression of and IFN--responsive genes ( and ) than kidneys of WT or mice did at this time point. Splenic T cells from untreated mice were hyperproliferative and produced more IFN- than did those of WT or mice. IFN- blocking antibody administered to mice or deletion of ( mice) blocked the protective effect of SphK2 deficiency in fibrosis. Moreover, adoptive transfer of (but not ) 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.
急性肾损伤（AKI）后的适应性修复不良可能导致进行性纤维化和肾功能下降。1-磷酸鞘氨醇在肾损伤及纤维化的多效性作用中发挥重要作用。我们研究了将鞘氨醇磷酸化生成1-磷酸鞘氨醇的鞘氨醇激酶1和2（SphK1和SphK2）在叶酸（FA）或单侧缺血再灌注损伤诱导的肾纤维化中的作用。对急性肾损伤14天后的Masson三色染色以及纤维化标志物蛋白和mRNA表达进行分析发现，野生型（WT）和[此处原文有缺失]小鼠比[此处原文有缺失]小鼠表现出更多的肾纤维化。此外，与经FA处理的[此处原文有缺失]小鼠的肾脏相比，经FA处理的WT和[此处原文有缺失]小鼠的肾脏有更多的免疫细胞浸润以及纤维化和炎症标志物的表达。相比之下，在这个时间点，[此处原文有缺失]小鼠的肾脏比WT或[此处原文有缺失]小鼠的肾脏表现出更高的[此处原文有缺失]和IFN-γ反应基因（[此处原文有缺失]和[此处原文有缺失]）表达。未经处理的[此处原文有缺失]小鼠的脾T细胞增殖过度，且比WT或[此处原文有缺失]小鼠的脾T细胞产生更多的IFN-γ。给[此处原文有缺失]小鼠注射IFN-γ阻断抗体或缺失[此处原文有缺失]（[此处原文有缺失]小鼠）可阻断SphK2缺乏对纤维化的保护作用。此外，将[此处原文有缺失]（而非[此处原文有缺失]）CD4 T细胞过继转移到WT小鼠中可阻断FA诱导的纤维化。最后，一种选择性SphK2抑制剂可阻断WT小鼠中FA诱导的肾纤维化。这些研究表明，抑制SphK2可能是减轻肾纤维化的一种新的治疗方法。
