Estrogen is renoprotective via a nonreceptor-dependent mechanism after cardiac arrest in vivo.
BACKGROUND
Severe ischemia induces renal injury less frequently in women than men. In this study, cardiac arrest and cardiopulmonary resuscitation were used to assess whether estradiol is renoprotective via an estrogen receptor (ER)-dependent mechanism.


METHODS
Male and female C57BL/6 and ER gene-deleted mice underwent 10 min of cardiac arrest followed by cardiopulmonary resuscitation. Serum chemistries and renal stereology were measured 24 h after arrest.


RESULTS
Estrogen did not affect mean arterial pressure, regional renal cortical blood flow, and arterial blood gases. Hence, female kidneys were protected (mean +/- SEM: blood urea nitrogen, 65+/- 21 vs.149+/- 27 mg/dl, P = 0.04; creatinine, 0.14 +/- 0.05 vs. 0.73 +/- 0.16 mg/dl, P = 0.01; volume of necrotic tubules, 7 +/- 1% vs. 10 +/- 0%, P = 0.04). Estrogen also reduced renal injury. In intact females (n = 5), ovariectomized/vehicle-treated (n = 8), and ovariectomized/estrogen-treated (n = 8) animals, blood urea nitrogen was 65 +/- 21, 166 +/- 28, and 50 +/- 14 mg/dl (P = 0.002); creatinine was 0.14 +/- 0.05, 0.74 +/- 0.26, and 0.23 +/- 0.27 mg/dl (P = 0.014); necrotic tubules were 2.5 +/- 0.25%, 12.0 +/- 1.9%, and 5.0 +/- 1.6% (P = 0.004), respectively. In ER-[alpha] and ER-[beta] gene-deleted mice and controls estradiol-reduced functional injury (blood urea nitrogen: estradiol 117 +/- 71, vehicle 167 +/- 56, P = 0.007; creatinine: estradiol 0.5 +/- 0.5, vehicle 1.0 +/- 0.4, P = 0.013), but the effect of estradiol was not different between ER-[alpha] or ER-[beta] gene-deleted mice. Adding ICI 182,780 to estradiol did not alter injury.


CONCLUSIONS
In women, kidneys were protected from cardiac arrest through estrogen. Estradiol-mediated renoprotection was not affected by ER deletion or blockade. Estradiol is renoprotective after cardiac arrest. The results indicate that estradiol renoprotection is ER-[alpha] and ER-[beta] independent.
Hutchens
Michael P
MP
Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road UHN-2, Portland, Oregon 97239, USA. hutchenm@ohsu.edu
Nakano
Takaaki
T
Kosaka
Yasuharu
Y
Dunlap
Jennifer
J
Zhang
Wenri
W
Herson
Paco S
PS
Murphy
Stephanie J
SJ
Anderson
Sharon
S
Hurn
Patricia D
PD
D000209:Acute-Phase Proteins / Q000378:metabolism / Q000652:urine; D000818:Animals; D001774:Blood Chemical Analysis; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology; D004967:Estrogens / Q000494:pharmacology* / Q000502:physiology*; D005260:Female; D006323:Heart Arrest / Q000150:complications*; D007668:Kidney / Q000473:pathology; D007672:Kidney Cortex / Q000098:blood supply; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism / Q000652:urine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000378:metabolism / Q000652:urine; D010052:Ovariectomy; D020011:Protective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control; D012727:Sex Characteristics
D000209:Acute-Phase Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D020011:Protective Agents; C071332:Lcn2 protein, mouse; D004958:Estradiol; D003404:Creatinine