title: Hypoxia-induced regulation of placental REDD1 and mTOR was impaired in a rat model of estrogen-induced cholestasis.
abstract: Hypoxia inducible factor-1α (HIF-1α), regulated in development and DNA damage response-1 (REDD1), and mammalian target of rapamycin (mTOR) play distinct roles in response to hypoxia. The aim of this study was to evaluate whether the HIF-1α-REDD1-mTOR-mediated hypoxic stress response also operates normally in estrogen-induced cholestasis.
  
  
  
  Pregnant rats were administered with ethinylestradiol (EE) to induce cholestasis and then were subjected to feto-placental ischemia reperfusion (IR); as controls, one group received neither EE nor IR, and another two groups received only EE or IR.
  
  
  
  Giving rats either EE alone or IR alone increased placental levels of HIF-1α, REDD1, glucose transporter-1 (GLUT1), and phosphoglycerate kinase-1 (PGK1), and decreased placental mTOR and lactic dehydrogenase A (LDHA) expression compared with the control rats. Subjecting EE-treated rats to IR did not further alter placental levels of REDD1 or mTOR, while it did elevate placental HIF-1α, GLUT1, and PGK1 expression, and decline LDHA expression. By contrast, mRNA levels did not differ significantly among the four groups for any of the proteins analyzed.
  
  
  
  This study manifested that placental HIF-1α and its downstream glucose metabolism effectors can effectively react to hypoxia in EE-induced cholestasis rats. However, hypoxia-induced REDD1 and mTOR alternation, which responds efficiently in normal placentas, was impaired in EE-induced cholestasis placentas.
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20, Renmin South Road, Section 3, Chengdu, 610041, Sichuan, China.|Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20, Renmin South Road, Section 3, Chengdu, 610041, Sichuan, China.
authors.forename: Huafang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20, Renmin South Road, Section 3, Chengdu, 610041, Sichuan, China.|Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Cell and Gene Therapy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, No. 20, Renmin South Road, Section 3, Chengdu, 610041, Sichuan, China. yayi.hu@163.com.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000818:Animals; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism*; D004195:Disease Models, Animal; D004997:Ethinyl Estradiol; D005260:Female; D005947:Glucose / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion / Q000379:methods; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C469992:Ddit4 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D004997:Ethinyl Estradiol; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: Cholestasis; Hypoxia inducible factor; Ischemia reperfusion; Mammalian target of rapamycin estrogen; Pregnant rat; Regulated in development and DNA damage response-1