title: Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner.
abstract: BACKGROUND
  There is a sex difference in the risk of ischemic acute kidney injury (AKI), and estrogen mediates the protective effect of female sex. We previously demonstrated that preprocedural chronic restoration of physiologic estrogen to ovariectomized female mice ameliorated AKI after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). In the present study, we hypothesized that male mice and aged female mice would benefit from estrogen administration after CA/CPR. We tested the effect of estrogen in a clinically relevant manner by administrating it after CA/CPR.
  
  
  METHODS
  CA/CPR was performed in young (10-15 weeks), middle-aged (43-48 weeks), and aged (78-87 weeks) C57BL/6 male and female mice. Mice received intravenous 17β-estradiol or vehicle 15 min after resuscitation. Serum chemistries and unbiased stereological assessment of renal injury were completed 24 h after CA. Regional renal cortical blood flow was measured by a laser Doppler, and renal levels of estrogen receptor alpha (ERα) and G protein-coupled estrogen receptor (GPER) were evaluated with immunoblotting.
  
  
  RESULTS
  Post-arrest estrogen administration reduced injury in young males without significant changes in renal blood flow (percentage reduction compared with vehicle: serum urea nitrogen, 30 %; serum creatinine (sCr), 41 %; volume of necrotic tubules (VNT), 31 %; P < 0.05). In contrast, estrogen did not affect any outcomes in young females. In aged mice, estrogen significantly reduced sCr (80 %) and VNT (73 %) in males and VNT (51 %) in females. Serum estrogen levels in aged female mice after CA/CPR were the same as levels in male mice. With age, renal ERα was upregulated in females.
  
  
  CONCLUSIONS
  Estrogen administration after resuscitation from CA ameliorates renal injury in young males and aged mice in both sexes. Because injury was small, young females were not affected. The protective effect of exogenous estrogen may be detectable with loss of endogenous estrogen in aged females and could be mediated by differences in renal ERs. Post-arrest estrogen administration is renoprotective in a sex- and age-dependent manner.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. ikeda@ohsu.edu.
authors.forename: Mizuko
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. tswide@lion.lmu.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Swide
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Joseph E. Walther Hall, R3 C400 980 W. Walnut St., Indianapolis, IN, 46202, USA. avayl@umail.iu.edu.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vayl
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Joseph E. Walther Hall, R3 C400 980 W. Walnut St., Indianapolis, IN, 46202, USA. tlahm@iu.edu.|Richard L. Roudebush VA Medical Center, 1481 W 10th St, Indianapolis, IN, 46202, USA. tlahm@iu.edu.
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. anderssh@ohsu.edu.
authors.forename: Sharon
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. hutchenm@ohsu.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hutchens
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control*; D000367:Age Factors; D000818:Animals; D001806:Blood Urea Nitrogen; D016887:Cardiopulmonary Resuscitation / Q000379:methods*; D003404:Creatinine / Q000097:blood; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000627:therapeutic use*; D005260:Female; D006323:Heart Arrest / Q000150:complications* / Q000188:drug therapy / Q000628:therapy; D007511:Ischemia / Q000150:complications / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012079:Renal Circulation / Q000187:drug effects; D012737:Sex Factors
chemical_list: D004967:Estrogens; D004958:Estradiol; D003404:Creatinine