title: Differential impact of glucose levels and advanced glycation end-products on tubular cell viability and pro-inflammatory/profibrotic functions.
abstract: High glucose (HG) or synthetic advanced glycation end-products (AGE) conditions are generally used to mimic diabetes in cellular models. Both models have shown an increase of apoptosis, oxidative stress and pro-inflammatory cytokine production in tubular cells. However, the impact of the two conditions combined has rarely been studied. In addition, the impact of glucose level variation due to cellular consumption is not clearly characterized in such experiments. Therefore, the aim of this study was to compare the effect of HG and AGE separately and of both on tubular cell phenotype changes in the HK2 cell line. Moreover, glucose consumption was monitored every hour to maintain the glucose level by supplementation throughout the experiments. We thus observed a significant decrease of apoptosis and H2O2 production in the HK2 cell. HG or AGE treatment induced an increase of total and mitochondrial apoptosis as well as TGF-β release compared to control conditions; however, AGE or HG led to apoptosis preferentially involving the mitochondria pathway. No cumulative effect of HG and AGE treatment was observed on apoptosis. However, a pretreatment with RAGE antibodies partially abolished the apoptotic effect of HG and completely abolished the apoptotic effect of AGE. In conclusion, tubular cells are sensitive to the lack of glucose as well as to the HG and AGE treatments, the AGE effect being more deleterious than the HG effect. Absence of a potential synergistic effect of HG and AGE could indicate that they act through a common pathway, possibly via the activation of the RAGE receptors.
authors.affiliation: Nephrology Clinic, Grenoble University Hospital, Grenoble F-38043, France; TIMC/Therex Laboratory, UMR 5525 (CNRS-UJF) Faculty of Medicine, Univ. Grenoble Alpes, Grenoble F-38041, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Franko
authors.affiliation: TIMC/Therex Laboratory, UMR 5525 (CNRS-UJF) Faculty of Medicine, Univ. Grenoble Alpes, Grenoble F-38041, France; Chronic Granulomatous Disease Diagnosis and Research Centre (CDiReC), Pôle Biologie, CHU de Grenoble, Grenoble F-38043, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Brault
authors.affiliation: Nephrology Clinic, Grenoble University Hospital, Grenoble F-38043, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jouve
authors.affiliation: TIMC/Therex Laboratory, UMR 5525 (CNRS-UJF) Faculty of Medicine, Univ. Grenoble Alpes, Grenoble F-38041, France; Chronic Granulomatous Disease Diagnosis and Research Centre (CDiReC), Pôle Biologie, CHU de Grenoble, Grenoble F-38043, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Beaumel
authors.affiliation: Department of Endocrinology, Grenoble University Hospital, Grenoble F-38043, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Benhamou
authors.affiliation: Nephrology Clinic, Grenoble University Hospital, Grenoble F-38043, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Zaoui
authors.affiliation: TIMC/Therex Laboratory, UMR 5525 (CNRS-UJF) Faculty of Medicine, Univ. Grenoble Alpes, Grenoble F-38041, France; Chronic Granulomatous Disease Diagnosis and Research Centre (CDiReC), Pôle Biologie, CHU de Grenoble, Grenoble F-38043, France. Electronic address: mjstasia@chu-grenoble.fr.
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Stasia
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005947:Glucose / Q000008:administration & dosage*; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology
chemical_list: D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D005947:Glucose
keywords: AGE; Diabetic nephropathy; Glucose; Inflammation; ROS; Tubular cells