title: Estrogen-mediated renoprotection following cardiac arrest and cardiopulmonary resuscitation is robust to GPR30 gene deletion.
abstract: BACKGROUND
  Acute kidney injury is a serious,sexually dimorphic perioperative complication, primarily attributed to hypoperfusion. We previously found that estradiol is renoprotective after cardiac arrest and cardiopulmonary resuscitation in ovariectomized female mice. Additionally, we found that neither estrogen receptor alpha nor beta mediated this effect. We hypothesized that the G protein estrogen receptor (GPR30) mediates the renoprotective effect of estrogen.
  
  
  METHODS
  Ovariectomized female and gonadally intact male wild-type and GPR30 gene-deleted mice were treated with either vehicle or 17β-estradiol for 7 days, then subjected to cardiac arrest and cardiopulmonary resuscitation. Twenty four hours later, serum creatinine and urea nitrogen were measured, and histologic renal injury was evaluated by unbiased stereology.
  
  
  RESULTS
  In both males and females, GPR30 gene deletion was associated with reduced serum creatinine regardless of treatment. Estrogen treatment of GPR30 gene-deleted males and females was associated with increased preprocedural weight. In ovariectomized female mice, estrogen treatment did not alter resuscitation, but was renoprotective regardless of GPR30 gene deletion. In males, estrogen reduced the time-to-resuscitate and epinephrine required. In wild-type male mice, serum creatinine was reduced, but neither serum urea nitrogen nor histologic outcomes were affected by estrogen treatment. In GPR30 gene-deleted males, estrogen did not alter renal outcomes. Similarly, renal injury was not affected by G1 therapy of ovariectomized female wild-type mice.
  
  
  CONCLUSIONS
  Treatment with 17β-estradiol is renoprotective after whole-body ischemia-reperfusion in ovariectomized female mice irrespective of GPR30 gene deletion. Treatment with the GPR30 agonist G1 did not alter renal outcome in females. We conclude GPR30 does not mediate the renoprotective effect of estrogen in ovariectomized female mice. In males, estrogen therapy was not renoprotective. Estrogen treatment of GPR30 gene-deleted mice was associated with increased preprocedural weight in both sexes. Of significance to further investigation, GPR30 gene deletion was associated with reduced serum creatinine, regardless of treatment.
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hutchens
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Kosaka
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Wenri
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Fujiyoshi
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Murphy
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Nabil
authors.initials: N
authors.lastname: Alkayed
authors.affiliation: Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Sharon
authors.initials: S
authors.lastname: Anderson
mesh_terms: D000818:Animals; D016887:Cardiopulmonary Resuscitation / Q000009:adverse effects; D019610:Cytoprotection / Q000187:drug effects* / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D017353:Gene Deletion; D006323:Heart Arrest / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: C532507:GPER1 protein, mouse; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol