ABSTRACT
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.
Keywords
Abbreviations:
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)To read this article in full you will need to make a payment
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REFERENCES
- Changing epidemiology of chronic kidney disease as a result of type 2 diabetes mellitus from 1990 to 2017: estimates from Global Burden of Disease 2017.J Diabetes Investig. 2021; 12: 346-356
- Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.N Engl J Med. 2008; 358: 2560-2572
- Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper-IgA mice.FASEB J. 2019; 33: 5181-5195
- Sphingosine-1-phosphate metabolism and signaling in kidney diseases.J Am Soc Nephrol. 2021; 32: 9-31
- Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces cisplatin-induced tubule injury.J Am Soc Nephrol. 2015; 26: 908-925
- Sphingosine kinase 1 protects against renal ischemia-reperfusion injury in mice by sphingosine-1-phosphate1 receptor activation.Kidney Int. 2011; 80: 1315-1327
- Inhibition of sphingosine 1-phosphate receptor 2 protects against renal ischemia-reperfusion injury.J Am Soc Nephrol. 2012; 23: 266-280
- The apoM/S1P complex-A mediator in kidney biology and disease?.Front Med (Lausanne). 2021; 8754490
- Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M.Proc Natl Acad Sci U S A. 2011; 108: 9613-9618
- Induction of insulin secretion by apolipoprotein M, a carrier for sphingosine 1-phosphate.Biochim Biophys Acta. 2014; 1841: 1217-1226
- HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation.Sci Signal. 2015; 8: ra79
- HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation.Nature. 2015; 523: 342-346
- Sphingosine 1-phosphate and atherosclerosis.J Atheroscler Thromb. 2018; 25: 16-26
- Plasma triglycerides and HDL-C levels predict the development of diabetic kidney disease in subjects with type 2 diabetes: the AMD annals initiative.Diabetes Care. 2016; 39: 2278-2287
- Prevention of diabetic nephropathy by tight target control in an Asian population with type 2 diabetes mellitus: a 4-year prospective analysis.Arch Intern Med. 2010; 170: 155-161
- Gender differences in the association between HDL cholesterol and the progression of diabetic kidney disease in type 2 diabetic patients.Nephrol Dial Transplant. 2012; 27: 1070-1075
- Protection against insulin resistance by Apolipoprotein M/Sphingosine-1-Phosphate.Diabetes. 2020; 69: 867-881
- Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes.Kidney Int. 2011; 79: 1090-1098
- High-density lipoprotein from end-stage renal disease patients exhibits superior cardioprotection and increase in sphingosine-1-phosphate.Eur J Clin Invest. 2018; 48: e12866
- Characteristics of lipid metabolism including serum apolipoprotein M levels in patients with primary nephrotic syndrome.Lipids Health Dis. 2017; 16: 167
- Apolipoprotein M in patients with chronic kidney disease.Atherosclerosis. 2018; 275: 304-311
- The effect of nephropathy on plasma sphingosine 1-phosphate concentrations in patients with type 2 diabetes.Clin Biochem. 2015; 48: 1264-1267
- Plasma ApoM levels and progression to kidney dysfunction in type 1 diabetics.Diabetes. 2022; 71: 1795-1799
- A new Classification of diabetic nephropathy 2014: a report from Joint Committee on diabetic nephropathy.J Diabetes Investig. 2015; 6: 242-246
- Apolipoprotein M protects lipopolysaccharide-treated mice from death and organ injury.Thromb Haemost. 2018; 118: 1021-1035
- Liver involvement in sphingosine 1-phosphate dynamism revealed by adenoviral hepatic overexpression of apolipoprotein M.Atherosclerosis. 2013; 229: 102-109
- Involvement of CETP (cholesteryl ester transfer protein) in the shift of sphingosine-1-phosphate among lipoproteins and in the modulation of its functions.Arterioscler Thromb Vasc Biol. 2017; 37: 506-514
- Establishment of a measurement system for sphingolipids in the cerebrospinal fluid based on liquid chromatography-tandem mass spectrometry, and its application in the diagnosis of carcinomatous meningitis.J Appl Lab Med. 2020; 5: 656-670
- Use of gas chromatography mass spectrometry to elucidate metabolites predicting the phenotypes of IgA nephropathy in hyper IgA mice.PLoS One. 2019; 14e0219403
- Stable expression of nephrin and localization to cell-cell contacts in novel murine podocyte cell lines.Kidney Int. 2004; 66: 91-101
- LDL receptor and ApoE are involved in the clearance of ApoM-associated sphingosine 1-phosphate.J Biol Chem. 2015; 290: 2477-2488
- N,N-dimethylsphingosine inhibition of sphingosine kinase and sphingosine 1-phosphate activity in human platelets.Biochemistry. 1996; 35: 626-633
- Sphingosine 1-phosphate-related metabolism in the blood vessel.J Biochem. 2005; 138: 47-55
- Modulation of sphingosine 1-phosphate by hepatobiliary cholesterol handling.FASEB J. 2020; 34: 14655-14670
- Analysis of mitochondrial function using phosphorescent oxygen-sensitive probes.Nat Protoc. 2006; 1: 2563-2572
- Increased mRNA levels of sphingosine kinases and S1P lyase and reduced levels of S1P were observed in hepatocellular carcinoma in association with poorer differentiation and earlier recurrence.PLoS One. 2016; 11e0149462
- Mitochondrial dysfunction in diabetic kidney disease.Clin Chim Acta. 2019; 496: 108-116
- Identification of the hydrophobic ligand binding pocket of the S1P1 receptor.J Biol Chem. 2007; 282: 2374-2385
- Crystal structure of a lipid G protein-coupled receptor.Science. 2012; 335: 851-855
- The structure and function of the S1P1 receptor.Trends Pharmacol Sci. 2013; 34: 401-412
- A novel human apolipoprotein (apoM).J Biol Chem. 1999; 274: 31286-31290
- Specific tissue expression and cellular localization of human apolipoprotein M as determined by in situ hybridization.Acta Histochem. 2003; 105: 67-72
- FTY720 attenuates angiotensin II-induced podocyte damage via inhibiting inflammatory cytokines.Mediators Inflamm. 2017; 20173701385
- Modulation of sphingosine-1-phosphate and apolipoprotein M levels in the plasma, liver and kidneys in streptozotocin-induced diabetic mice.J Diabetes Investig. 2014; 5: 639-648
- Glycation of HDL polymerizes apolipoprotein M and attenuates its capacity to bind to sphingosine 1-phosphate.J Atheroscler Thromb. 2021; 28: 730-741
- HDL in diabetic nephropathy has less effect in endothelial repairing than diabetes without complications.Lipids Health Dis. 2016; 15: 76
- Animal models of diabetes-associated renal injury.J Diabetes Res. 2020; 20209416419
- LC-MS-based untargeted metabolomics reveals early biomarkers in STZ-induced diabetic rats with cognitive impairment.Front Endocrinol (Lausanne). 2021; 12665309
- Endothelial-specific loss of sphingosine-1-phosphate receptor 1 increases vascular permeability and exacerbates bleomycin-induced pulmonary fibrosis.Am J Respir Cell Mol Biol. 2022; 66: 38-52
- HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver.JCI Insight. 2016; 1: e87058
- Aging suppresses sphingosine-1-phosphate chaperone ApoM in circulation resulting in maladaptive organ repair.Dev Cell. 2020; 53 (e4): 677-690
- Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1.FASEB J. 2016; 30: 2351-2359
- High-density lipoprotein-associated apolipoprotein m limits endothelial inflammation by delivering sphingosine-1-phosphate to the sphingosine-1-phosphate receptor 1.Arterioscler Thromb Vasc Biol. 2017; 37: 118-129
- Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta.Elife. 2020; 9: e52690
- Circulating cord blood HDL-S1P complex preserves the integrity of the feto-placental vasculature.Biochim Biophys Acta Mol Cell Biol Lipids. 2020; 1865158632
- Endothelial Spns2 and ApoM regulation of vascular tone and hypertension via sphingosine-1-phosphate.J Am Heart Assoc. 2021; 10e021261
- Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents.Hepatology. 2012; 56: 1427-1438
- Discovery and optimization of orally bioavailable phthalazone and cinnolone carboxylic acid derivatives as S1P2 antagonists against fibrotic diseases.J Med Chem. 2021; 64: 14557-14586
- Sphingosine 1-phosphate, a potential target in neovascular retinal disease.Br J Ophthalmol. 2022; 106: 1187-1195
- Inhibition of S1P Receptor 2 attenuates endothelial dysfunction and inhibits atherogenesis in Apolipoprotein E-deficient mice.J Atheroscler Thromb. 2021; 28: 630-642
- Mitochondrial dysfunction and diabetic nephropathy: nontraditional therapeutic opportunities.J Diabetes Res. 2021; 20211010268
- SIRT1-FOXOs activity regulates diabetic complications.Pharmacol Res. 2022; 175106014
- Resveratrol exerts a biphasic effect on apolipoprotein M.Br J Pharmacol. 2016; 173: 222-233
- Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate.Science. 2009; 325: 1254-1257
- Megalin is a receptor for apolipoprotein M, and kidney-specific megalin-deficiency confers urinary excretion of apolipoprotein M.Mol Endocrinol. 2006; 20: 212-218
Article info
Publication history
Published online: February 16, 2023
Accepted:
February 13,
2023
Received in revised form:
January 10,
2023
Received:
September 22,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
