title: Increased sphingosine 1-phosphate mediates inflammation and fibrosis in tubular injury in diabetic nephropathy.
abstract: Hyperglycemia induces all isoforms of transforming growth factor β (TGFβ), which in turn play key roles in inflammation and fibrosis that characterize diabetic nephropathy. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid, derived from sphingosine by the action of sphingosine kinase (SK). S1P mediates many biological processes, which mimic TGFβ signaling. To determine the role of SK1 and S1P in inducing fibrosis and inflammation, and the interaction with TGFβ-1, 2 and 3 signalling in diabetic nephropathy, human proximal tubular cells (HK2 cells) were exposed to normal (5 mmol/L) or high (30 mmol/L) glucose or TGFβ-1, -2, -3 ± an SK inhibitor (SKI-II) or SK1 siRNA. Control and diabetic wild type (WT) and SK1(-/-) mice were studied. Fibrotic and inflammatory markers, and relevant downstream signalling pathways were assessed. SK1 mRNA and protein expression was increased in HK2 cells exposed to high glucose or TGFβ1,-2,-3. All TGFβ isoforms induced fibronectin, collagen IV and macrophage chemoattractant protein 1 (MCP1), which were reversed by both SKI-II and SK1 siRNA. Exposure to S1P increased phospho-p44/42 expression, AP-1 binding and NFkB phosphorylation. WT diabetic mice exhibited increased renal cortical S1P, fibronectin, collagen IV and MCP1 mRNA and protein expression compared to SK1(-/-) diabetic mice. In summary, this study demonstrates that inhibiting the formation of S1P reduces tubulointerstitial renal inflammation and fibrosis in diabetic nephropathy.
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Dania
authors.initials: D
authors.lastname: Yaghobian
authors.affiliation: Department of Medicine, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Don
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Sarina
authors.initials: S
authors.lastname: Yaghobian
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Xinming
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
authors.affiliation: Department of Medicine, Kolling Institute of Medical Research, University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Saad
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; D008246:Lysophospholipids; D016328:NF-kappa B; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: diabetes; fibrosis; nephropathy; sphingosine kinase