title: Involvement of hypoxia-inducible factor-1α in the oxidative stress induced by advanced glycation end products in murine Leydig cells.
abstract: Hyperglycemia increases the formation of advanced glycation end products (AGEs), triggers oxidative impairments and influences inducible factor (HIF)-1α protein levels and transactivation function. Compromised HIF-1α in testis leads to male infertility. The aim of the study was to investigate the role of HIF-1α in oxidative stress induced by AGEs in murine Leydig TM3 cells. TM3 cells were treated with 50 μg/ml of AGEs, or HIF-1α siRNA or 500 μM of DMOG (dimethyloxalylglycine) respectively. The cells were also pretreated with HIF-1α siRNA or 500 μM of DMOG and then were treated with 50 μg/ml of AGEs. The formation of reactive oxygen species (ROS) and cell apoptosis was evaluated. The expression of caspase-3, Heme oxygenase (HO)-1, steroidogenic acute regulatory protein (StAR) and cytochrome P450 17α polypeptide 1 (CYP17A1) was examined by Western blotting. AGEs increased ROS production, induced apoptosis and activated HIF-1α and HO-1 in TM3 cells. HIF-1α attenuated the AGE-induced ROS formation and promoted apoptosis via the upregulation of caspase-3. Knockdown of HIF-1α inhibited the expression of CYP17A1 and StAR, and enhanced the inhibition of StAR and CYP17A1 by AGEs. These findings indicate that attenuated HIF-1α exacerbates the oxidative stress injury by AGEs in murine Leydig cells, and contributes to diabetic male infertility.
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China. Electronic address: chenying9851231@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, No.2 Yanghe No. 2 Village, Jiangbei District, Chongqing 400020, China. Electronic address: zhangyicq11@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, the First Hospital of Jilin University, No.3302 Jilin Road, Erdao District, Changchun 130032, China. Electronic address: jihf@jlu.edu.cn.
authors.forename: Huifan
authors.initials: H
authors.lastname: Ji
authors.affiliation: Key Laboratory of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, No.2 Yanghe No. 2 Village, Jiangbei District, Chongqing 400020, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Key Laboratory of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, No.2 Yanghe No. 2 Village, Jiangbei District, Chongqing 400020, China.
authors.forename: Jigao
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, No.2 Yanghe No. 2 Village, Jiangbei District, Chongqing 400020, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Key Laboratory of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, No.2 Yanghe No. 2 Village, Jiangbei District, Chongqing 400020, China.
authors.forename: Daguang
authors.initials: D
authors.lastname: Sun
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D000600:Amino Acids, Dicarboxylic; D017127:Glycation End Products, Advanced; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000098682:Steroidogenic Acute Regulatory Protein; D051547:Heme Oxygenase-1; D013254:Steroid 17-alpha-Hydroxylase; D053148:Caspase 3; C040947:oxalylglycine
keywords: Advanced glycation end products; HIF-1α; Leydig cell; Reactive oxygen species