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Bone marrow stromal cell antigen-1 (CD157) regulated by sphingosine kinase 2 mediates kidney fibrosis
Tsuyoshi Inoue1,2, Yasuna Nakamura2, Shinji Tanaka1
1Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, United States.
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.
Insights
Sphingosine kinase 2 (SphK2) epigenetically regulates kidney fibrosis by altering Bst1/CD157 expression. SphK2 deficiency reduces renal fibrosis, highlighting Bst1 as a key therapeutic target for chronic kidney disease.
Area of Science:
- Nephrology
- Epigenetics
- Molecular Biology
Background:
- Chronic kidney disease (CKD) is characterized by progressive renal fibrosis, with limited therapeutic options.
- Sphingosine kinase 2 (SphK2) plays a role in kidney fibrosis, potentially through epigenetic mechanisms.
- SphK2 produces sphingosine 1-phosphate (S1P), which influences histone acetylation and gene expression.
Purpose of the Study:
- To investigate the epigenetic role of SphK2 in regulating kidney fibrosis.
- To identify downstream genes regulated by SphK2-mediated epigenetic changes in the context of renal fibrosis.
- To determine the specific role of Bst1/CD157 in kidney fibrosis development.
Main Methods:
- Comprehensive analysis using RNA-sequencing (RNA-seq) and ChIP-sequencing (ChIP-seq).
- Assessment of renal fibrosis in Sphk2-deficient and Bst1-deficient mouse models.
- Evaluation of unilateral ischemia-reperfusion injury as a model for kidney fibrosis.
Main Results:
- Sphingosine kinase 2 (SphK2) epigenetically regulates Bst1/CD157 expression via histone acetylation.
- Mice deficient in Bst1 (Bst1-/-) exhibited reduced renal fibrosis following injury.
- SphK2 deficiency (Sphk2-/-) also led to decreased fibrosis in kidney injury models.
Conclusions:
- Bst1/CD157 is identified as a novel SphK2-regulated gene critical for kidney fibrosis.
- SphK2-mediated epigenetic regulation of Bst1 is a key driver of renal fibrosis.
- Targeting the SphK2-Bst1 pathway offers a potential therapeutic strategy for mitigating kidney fibrosis in CKD.
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