title: Aryl Hydrocarbon Receptor Deficiency Attenuates Oxidative Stress-Related Mesangial Cell Activation and Macrophage Infiltration and Extracellular Matrix Accumulation in Diabetic Nephropathy.
abstract: OBJECTIVE
  Activation of glomerular mesangial cells (MCs) and functional changes of renal tubular cells are due to metabolic abnormalities, oxidative stress, and matrix accumulation in the diabetic nephropathy (DN). Aryl hydrocarbon receptor (AhR) activation has been implicated in DN. In this study, we investigated the role of AhR in the pathophysiological processes of DN using AhR knockout (AhRKO) and pharmacological inhibitor α-naphthoflavone mouse models.
  
  
  RESULTS
  The increased blood glucose, glucose intolerance, MC activation, macrophage infiltration, and extracellular matrix (ECM) accumulation were significantly attenuated in AhRKO mice with diabetic inducer streptozotocin (STZ) treatment. AhR deficiency by genetic knockout or pharmacological inhibition also decreased the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2(PGE2), lipid peroxidation, oxidative stress, NADPH oxidase activity, and N-ɛ-carboxymethyllysine (CML, a major advanced glycation end product) in STZ-induced diabetic mice. CML showed remarkably increased AhR/COX-2 DNA-binding activity, protein-DNA interactions, gene regulation, and ECM formation in MCs and renal proximal tubular cells, which could be reversed by siRNA-AhR transfection. CML-increased AhR nuclear translocation and biological activity in MCs and renal proximal tubular cells could also be effectively attenuated by antioxidants.
  
  
  METHODS
  We elucidate for the first time that AhR plays an important role in MC activation, macrophage infiltration, and ECM accumulation in DN conferred by oxidative stress.
  
  
  CONCLUSIONS
  AhR-regulated COX-2/PGE2expression and ECM deposition through oxidative stress cascade is involved in the CML-triggered MC activation and macrophage infiltration. These findings suggest new insights into the development of therapeutic approaches to reduce diabetic microvascular complications. Antioxid. Redox Signal. 24, 217-231.
authors.affiliation: 1 Department of Medical Research, Taichung Veterans General Hospital , Taichung, Taiwan .
authors.forename: Wen-Jane
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: 2 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan .|3 Department of Medical Research, China Medical University Hospital, China Medical University , Taichung, Taiwan .
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
authors.affiliation: 2 Institute of Toxicology, College of Medicine, National Taiwan University , Taipei, Taiwan .|4 Department of Internal Medicine, University Hospital and College of Medicine, National Taiwan University , Taipei, Taiwan .
authors.forename: Chih-Kang
authors.initials: CK
authors.lastname: Chiang
authors.affiliation: 5 Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital , Taichung, Taiwan .
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.affiliation: 6 Cardiovascular Center, Taichung Veterans General Hospital , Taichung, Taiwan .
authors.forename: Kae-Woei
authors.initials: KW
authors.lastname: Liang
authors.affiliation: 7 Department of Internal Medicine, Taichung Veterans General Hospital , Chiayi, Taiwan .|8 Department of Life Science, Tunghai University , Taichung, Taiwan .|9 School of Medicine, College of Medicine, China Medical University , Taichung, Taiwan .|10 Division of Nephrology, Taichung Veterans General Hospital , Taichung, Taiwan .
authors.forename: Cheng-Hsu
authors.initials: CH
authors.lastname: Chen
authors.affiliation: 11 Institute of Biomedical Sciences, National Chung Hsing University , Taichung, Taiwan .
authors.forename: Hsing-Ru
authors.initials: HR
authors.lastname: Tien
authors.affiliation: 1 Department of Medical Research, Taichung Veterans General Hospital , Taichung, Taiwan .
authors.forename: Pei-Hsuan
authors.initials: PH
authors.lastname: Chen
authors.affiliation: 1 Department of Medical Research, Taichung Veterans General Hospital , Taichung, Taiwan .
authors.forename: Jen-Pey
authors.initials: JP
authors.lastname: Wu
authors.affiliation: 1 Department of Medical Research, Taichung Veterans General Hospital , Taichung, Taiwan .
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: 11 Institute of Biomedical Sciences, National Chung Hsing University , Taichung, Taiwan .
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Lai
authors.affiliation: 11 Institute of Biomedical Sciences, National Chung Hsing University , Taichung, Taiwan .
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Chang
authors.affiliation: 5 Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital , Taichung, Taiwan .|11 Institute of Biomedical Sciences, National Chung Hsing University , Taichung, Taiwan .|12 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University , Taichung, Taiwan .
authors.forename: Wayne Huey-Herng
authors.initials: WH
authors.lastname: Sheu
authors.affiliation: 1 Department of Medical Research, Taichung Veterans General Hospital , Taichung, Taiwan .|11 Institute of Biomedical Sciences, National Chung Hsing University , Taichung, Taiwan .|12 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University , Taichung, Taiwan .
authors.forename: Meei-Ling
authors.initials: ML
authors.lastname: Sheu
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000235:genetics; D001571:Benzoflavones / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency* / Q000235:genetics; D013311:Streptozocin
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001571:Benzoflavones; D001786:Blood Glucose; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D013311:Streptozocin; C484722:Ahr protein, mouse; C011512:alpha-naphthoflavone