Data_Sheet_1_Bone marrow stromal cell antigen-1 (CD157) regulated by sphingosine kinase 2 mediates kidney fibrosis.docx

Chronic kidney disease is a progressive disease that may lead to end-stage renal disease. Interstitial fibrosis develops as the disease progresses. Therapies that focus on fibrosis to delay or reverse progressive renal failure are limited. We and others showed that sphingosine kinase 2-deficient mice (Sphk2–/–) develop less fibrosis in mouse models of kidney fibrosis. Sphingosine kinase2 (SphK2), one of two sphingosine kinases that produce sphingosine 1-phosphate (S1P), is primarily located in the nucleus. S1P produced by SphK2 inhibits histone deacetylase (HDAC) and changes histone acetylation status, which can lead to altered target gene expression. We hypothesized that Sphk2 epigenetically regulates downstream genes to induce fibrosis, and we performed a comprehensive analysis using the combination of RNA-seq and ChIP-seq. Bst1/CD157 was identified as a gene that is regulated by SphK2 through a change in histone acetylation level, and Bst1–/– mice were found to develop less renal fibrosis after unilateral ischemia-reperfusion injury, a mouse model of kidney fibrosis. Although Bst1 is a cell-surface molecule that has a wide variety of functions through its varied enzymatic activities and downstream intracellular signaling pathways, no studies on the role of Bst1 in kidney diseases have been reported previously. In the current study, we demonstrated that Bst1 is a gene that is regulated by SphK2 through epigenetic change and is critical in kidney fibrosis.

慢性肾脏病是一种渐进性疾病，可能发展为终末期肾病。随着病情的进展，间质性纤维化逐渐形成。针对纤维化进行治疗以延缓或逆转渐进性肾衰竭的疗法较为有限。我们及他人研究发现，Sphingosine激酶2缺陷小鼠（Sphk2–/–）在肾脏纤维化小鼠模型中纤维化程度较低。Sphingosine激酶2（SphK2）是产生Sphingosine 1-磷酸（S1P）的两种鞘氨醇激酶之一，主要位于细胞核中。由SphK2产生的S1P可以抑制组蛋白脱乙酰化酶（HDAC）并改变组蛋白乙酰化状态，从而可能导致靶基因表达的改变。我们假设Sphk2通过表观遗传学调控下游基因以诱导纤维化，并采用RNA测序和ChIP测序的组合进行了全面分析。Bst1/CD157被鉴定为一种通过改变组蛋白乙酰化水平受到SphK2调控的基因，且Bst1–/–小鼠在单侧缺血再灌注损伤后，即肾脏纤维化小鼠模型中，纤维化程度较低。尽管Bst1是一种具有广泛功能、通过其多种酶活性和下游细胞内信号通路发挥作用的细胞表面分子，但此前尚未有关于Bst1在肾脏疾病中作用的研究报道。在本研究中，我们证明了Bst1是一种通过表观遗传学改变受SphK2调控的基因，并在肾脏纤维化中发挥关键作用。