title: NKT cell modulates NAFLD potentiation of metabolic oxidative stress-induced mesangial cell activation and proximal tubular toxicity.
abstract: Obesity and nonalcoholic fatty liver disease (NAFLD) are associated with the development and progression of chronic kidney disease. We recently showed that NAFLD induces liver-specific cytochrome P-450 (CYP)2E1-mediated metabolic oxidative stress after administration of the CYP2E1 substrate bromodichloromethane (BDCM) (Seth RK, Das S, Kumar A, Chanda A, Kadiiska MB, Michelotti G, Manautou J, Diehl AM, Chatterjee S. Toxicol Appl Pharmacol 274: 42-54, 2014; Seth RK, Kumar A, Das S, Kadiiska MB, Michelotti G, Diehl AM, Chatterjee S. Toxicol Sci 134:291-303, 2013). The present study examined the effects of CYP2E1-mediated oxidative stress in NAFLD leading to kidney toxicity. Mice were fed a high-fat diet for 12 wk to induce NAFLD. NAFLD mice were exposed to BDCM, a CYP2E1 substrate, for 4 wk. NAFLD + BDCM increased CYP2E1-mediated lipid peroxidation in proximal tubular cells compared with mice with NAFLD alone or BDCM-treated lean mice, thus ruling out the exclusive role of BDCM. Lipid peroxidation increased IL-1β, TNF-α, and interferon-γ. In parallel, mesangial cell activation was observed by increased α-smooth muscle actin and transforming growth factor-β, which was blocked by the CYP2E1 inhibitor diallyl sulphide both in vivo and in vitro. Mice lacking natural killer T cells (CD1d knockout mice) showed elevated (>4-fold) proinflammatory mediator release, increased Toll-like receptor (TLR)4 and PDGF2 mRNA, and mesangial cell activation in the kidney. Finally, NAFLD CD1D knockout mice treated with BDCM exhibited increased high mobility group box 1 and Fas ligand levels and TUNEL-positive nuclei, indicating that higher cell death was attenuated in TLR4 knockout mice. Tubular cells showed increased cell death and cytokine release when incubated with activated mesangial cells. In summary, an underlying condition of progressive NAFLD causes renal immunotoxicity and aberrant glomerular function possibly through high mobility group box 1-dependent TLR4 signaling and mesangial cell activation, which, in turn, is modulated by intrinsic CD1D-dependent natural killer T cells.
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Firas
authors.initials: F
authors.lastname: Alhasson
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Diptadip
authors.initials: D
authors.lastname: Dattaroy
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Suvarthi
authors.initials: S
authors.lastname: Das
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Varun
authors.initials: V
authors.lastname: Chandrashekaran
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Ratanesh Kumar
authors.initials: RK
authors.lastname: Seth
authors.affiliation: Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
authors.affiliation: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina; and schatt@mailbox.sc.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005355:Fibrosis; D024243:HMGB1 Protein / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007674:Kidney Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology* / Q000276:immunology; D008297:Male; D050527:Mesangial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000276:immunology; D018384:Oxidative Stress; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D022882:Trihalomethanes / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D018836:Inflammation Mediators; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D022882:Trihalomethanes; C025191:bromodichloromethane; D019392:Cytochrome P-450 CYP2E1
keywords: 4-hydroxynonenal; CD1d; Toll-like receptor 4; Vα14; chemokine (C-X-C motif) ligand 16; high mobility group box 1; natural killer T cells; nonalcoholic fatty liver disease