Abstract: SA-OR083

Bone Marrow Stromal Cell Antigen-1 Identified by RNA-Seq and ChIP-Seq Is important for Inducing Renal Ischemia-Reperfusion Injury and Fibrosis

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic


  • Inoue, Tsuyoshi, University of Virginia, Charlottesville, Virginia, United States
  • Huang, Liping, University of Virginia, Charlottesville, Virginia, United States
  • Rosin, Diane L., University of Virginia, Charlottesville, Virginia, United States
  • Ishihara, Katsuhiko, Kawasaki Medical School, Kurashiki, Japan
  • Wada, Youichiro, University of Tokyo, Tokyo, Japan
  • Okusa, Mark D., University of Virginia, Charlottesville, Virginia, United States

Sphingosine kinase 2-deficient mice (SphK2KO) develop less fibrosis after unilateral kidney ischemia-reperfusion injury (IRI). Sphingosine 1-phosphate (S1P) produced by SphK2 inhibits histone deacetylase (HDAC) and changes in histone acetylation status, which can lead to an altered target gene expression. The aim of this study is to elucidate new mechanisms of kidney fibrosis through epigenetic changes.


RNA-seq and ChIP-seq of H3K9ac and H3K27ac using primary renal fibroblasts from WT, Sphk1KO and Sphk2KO mice were performed. Flow cytometry was used to identify bone marrow stromal cell antigen-1 (BST-1/CD157) expression in hematopoietic cells. In addition, bone marrow chimeric mice were created to evaluate the role of BST-1 in bone marrow-derived cells. Unilateral IRI was used as a renal fibrosis model and bilateral IRI was used as an acute kidney injury (AKI) model.


The combination of RNA-seq and ChIP-seq analysis yielded 30 candidate genes that might be regulated by SphK2 through epigenetic change. We applied SphK2 knock down to WT fibroblasts and overexpression to fibroblasts from SphK2KO to determine if the selected genes are regulated by SphK2. Gene expression was also evaluated using an in vivo fibrosis model. Bst1 was identified as a gene that is regulated by SphK2 through a change in histone acetylation level. Bst1-deficient mice (Bst1KO) developed less fibrosis after renal unilateral IRI and were protected against renal bilateral IRI in the AKI model. Bone marrow chimera experiments further revealed that BST-1 expression on hematopoietic, but not parenchymal cells, is responsible for inducing renal IRI and fibrosis. BST-1 was found mainly in B cells and neutrophils by flow cytometry of spleen and bone marrow. The migration of neutrophils from Bst1KO was suppressed, and adoptive transfer of neutrophils from Bst1WT mice abolished the renal protective effect in Bst1KO mice.


Bst1 is a gene that is regulated by SphK2 through epigenetic change and is critical in kidney injury and fibrosis. Bst1KO mice are protected against renal IRI and develop less fibrosis. Furthermore Bst1 expression in neutrophils plays an important role in inducing renal ischemia-reperfusion injury and fibrosis.


  • NIDDK Support