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Apolipoprotein M/sphingosine 1-phosphate protects against diabetic nephropathy

  • Makoto Kurano
    Reprint requests: Makoto Kurano, Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
    Department of Clinical Laboratory Medicine and 5Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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  • Kazuhisa Tsukamoto
    Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
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  • Tomo Shimizu
    Tsukuba Research Institute, Research & Development Division, Sekisui Medical Co., Ltd., Ibaraki, Japan;
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  • Masumi Hara
    Department of Internal Medicine, Mizonokuchi Hospital, Teikyo University School of Medicine, Kanagawa, Japan
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  • Yutaka Yatomi
    Department of Clinical Laboratory Medicine and 5Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Published:February 16, 2023DOI:


      Diabetic nephropathy remains a common cause of end-stage renal failure and its associated mortality around the world. Sphingosine 1-phosphate (S1P) is a multifunctional lipid mediator and binds to HDL via apolipoprotein M (ApoM). Since HDL has been reported to be epidemiologically associated with kidney disease, we attempted to investigate the involvement of the ApoM/S1P axis in the pathogenesis/progression of diabetic nephropathy. In type 2 diabetic patients, the serum ApoM levels were inversely correlated with the clinical stage of diabetic nephropathy. The decline in the eGFR over a 5-year observation period proceeded more rapidly in subjects with lower serum ApoM levels. In a mouse model of streptozotocin-induced diabetes, deletion of ApoM deteriorated the phenotypes of diabetic nephropathy: the urinary albumin and plasma creatinine levels increased, the kidneys enlarged, and renal fibrosis and thickening of the basement membrane progressed. On the other hand, overexpression of ApoM ameliorated these phenotypes. These protective effects of ApoM were partially inhibited by treatment with VPC23019, an antagonist of S1P1 and S1P3, but not by treatment with JTE013, an antagonist of S1P2. ApoM/S1P axis attenuated activation of the Smad3 pathway, while augmented eNOS phosphorylation through the S1P1 pathway. Moreover, ApoM/S1P increased the SIRT1 protein levels and enhanced mitochondrial functions by increasing the S1P content of the cell membrane, which might cause selective activation of S1P1. ApoM might be a useful biomarker for predicting the progression of diabetic nephropathy, and the ApoM/S1P–S1P1 axis might serve as a novel therapeutic target for preventing the development/progression of diabetic nephropathy.



      ANOVA (analysis of variance), ApoM (apolipoprotein M), ApoM-knockdown mice (mice injected with siRNA against murine ApoM), ApoM-KO mice (ApoM knockout mice), ApoM mice (mice injected with an adenoviral vector encoding human ApoM), BMI (body mass index), CM-ApoM (conditioned medium of ApoM-overexpressing HepG2 cells), CM-Null (conditioned medium of HepG2 infected with blank adenovirus), Cre (creatinine), eGFR (estimated glomerular filtration rate), ELISA (enzyme linked immunosolvent assay), GFP (green fluorescent protein), GFP mice (mice injected with an adenoviral vector encoding GFP), HbA1c (glycosylated hemoglobin A1c), HDL (high-density lipoprotein), HFD (high-fat diet), JTE (JTE013), KO (knockout), LDL (low-density lipoprotein), N.S. (not significant), PAS (periodic acid-Schiff), PBS (phosphate-buffered saline), siCtl (control siRNA), S1P (sphingosine 1-phosphate), S1P1 (S1P receptor 1), S1P2 (S1P receptor 2), S1P3 (S1P receptor 3), SD (standard deviation), STZ (streptozotocin), TCA (tricarboxylic acid), TEM (transmission electron microscopy), VPC (VPC23019), WT mice (wild-type mice)
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