title: Double antioxidant activities of rosiglitazone against high glucose-induced oxidative stress in hepatocyte.
abstract: Chronic hyperglycemia is the hallmark of diabetes and its complication. High glucose-induced excessive reactive oxygen species (ROS) production has been considered to play an important role in the development of diabetes. However, the influence of high glucose on the liver remains to be clarified. Rosiglitazone (RSG) is a member of thiazolidinediones (TDZs) family, which is the ligand of the of nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPARγ), being used clinically for the treatment of type 2 diabetic patients through their insulin-sensitizing effect. In the present study, we investigated the cytotoxicity of high glucose in QZG hepatocytes and evaluated the protective effect of RSG. The results showed that high glucose significantly reduced cell viability through generation of ROS via activation of PKC, which was inhibited by RSG. On the one hand, RSG notably inhibited the activation of PKC induced by high glucose independent of PPARγ, leading to the decrease of ROS generation. On the other hand, RSG notably increased the expression of key antioxidant transcription factor Nrf2 and antioxidant enzyme HO-1 in a PPARγ-dependent manner, leading to the elimination of excessive ROS. In addition, RSG also inhibited the decrease of COX-2 expression induced by high glucose through activating PPARγ. Furthermore, the activation of Akt and MAPKs was involved in the effect of RSG on Nrf2, HO-1 and COX-2. In summary, our study supports the hypothesis that RSG protect hepatocytes from high glucose-induced toxicity through PPARγ-dependent and PPARγ-independent pathways.
authors.affiliation: Department of Toxicology, Faculty of Preventive Medicine, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Jiang Z
authors.initials: JZ
authors.lastname: Liu
authors.forename: Jun X
authors.initials: JX
authors.lastname: Hu
authors.forename: Hong L
authors.initials: HL
authors.lastname: Chen
authors.forename: Wen L
authors.initials: WL
authors.lastname: Li
authors.forename: Chun X
authors.initials: CX
authors.lastname: Hai
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D005947:Glucose