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.

慢性肾病是一种渐进性疾病，可能导致终末期肾病。随着疾病的进展，间质纤维化逐渐形成。针对纤维化治疗以延缓或逆转渐进性肾功能衰竭的方案颇为有限。我们及他人在小鼠肾脏纤维化模型中发现，缺乏鞘氨醇激酶2（Sphk2–/–）的小鼠较易产生较少的纤维化。鞘氨醇激酶2（SphK2）是产生鞘氨醇1-磷酸（S1P）的两种鞘氨醇激酶之一，其主要位于细胞核内。由SphK2产生的S1P可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，并利用RNA测序和ChIP测序的组合方法进行了全面分析。Bst1/CD157被鉴定为SphK2通过改变组蛋白乙酰化水平调控的基因，而在单侧缺血再灌注损伤（肾脏纤维化小鼠模型）后，Bst1–/–小鼠表现出较少的肾脏纤维化。尽管Bst1是一种具有广泛功能（通过其多样的酶活性及下游细胞内信号通路）的细胞表面分子，但之前尚未有关于Bst1在肾脏疾病中作用的报道。在本研究中，我们证实Bst1是一种受SphK2通过表观遗传学改变调控的基因，且在肾脏纤维化过程中扮演着至关重要的角色。