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

Tsuyoshi Inoue; Yasuna Nakamura; Shinji Tanaka; Takahide Kohro; Lisa X Li; Liping Huang; Junlan Yao; Suzuka Kawamura; Reiko Inoue; Hiroshi Nishi; Daichi Fukaya; Rie Uni; Sho Hasegawa; Reiko Inagi; Ryusuke Umene; Chia-Hsien Wu; Hong Ye; Amandeep Bajwa; Diane L Rosin; Katsuhiko Ishihara; Masaomi Nangaku; Youichiro Wada; Mark D Okusa

doi:10.3389/fmed.2022.993698

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

Front Med (Lausanne). 2022 Oct 4:9:993698. doi: 10.3389/fmed.2022.993698. eCollection 2022.

Authors

Tsuyoshi Inoue^{1

2}, Yasuna Nakamura², Shinji Tanaka¹, Takahide Kohro³, Lisa X Li¹, Liping Huang¹, Junlan Yao¹, Suzuka Kawamura¹, Reiko Inoue⁴, Hiroshi Nishi⁴, Daichi Fukaya⁴, Rie Uni⁴, Sho Hasegawa⁵, Reiko Inagi⁵, Ryusuke Umene², Chia-Hsien Wu², Hong Ye¹, Amandeep Bajwa¹, Diane L Rosin⁶, Katsuhiko Ishihara⁷, Masaomi Nangaku⁴, Youichiro Wada⁸, Mark D Okusa¹

Affiliations

¹ Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, United States.
² Department of Physiology of Visceral Function and Body Fluid, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
³ Department of Clinical Informatics/Cardiology, Jichi Medical University, Tochigi, Japan.
⁴ Division of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁵ Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Department of Pharmacology, University of Virginia, Charlottesville, VA, United States.
⁷ Department of Immunology and Molecular Genetics, Kawasaki Medical School, Okayama, Japan.
⁸ Isotope Science Center, The University of Tokyo, Tokyo, Japan.

Abstract

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.

Keywords: ADP-ribosyl cyclase; BST-1/CD157; GPI-linked proteins; fibrosis; kidney.

Abstract

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