Ikeda Mizuko, Swide Thomas, Vayl Alexandra, Lahm Tim, Anderson Sharon, Hutchens Michael P
Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
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.
Crit Care. 2015 Sep 18;19(1):332. doi: 10.1186/s13054-015-1049-8.
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.
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.
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.
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.
缺血性急性肾损伤（AKI）的风险存在性别差异，雌激素介导了女性的保护作用。我们之前证明，对卵巢切除的雌性小鼠进行术前生理性雌激素的慢性恢复可改善心脏骤停和心肺复苏（CA/CPR）后的AKI。在本研究中，我们假设雄性小鼠和老年雌性小鼠在CA/CPR后给予雌激素会受益。我们通过在CA/CPR后给予雌激素，以临床相关的方式测试了其效果。
对年轻（10 - 15周）、中年（43 - 48周）和老年（78 - 87周）的C57BL/6雄性和雌性小鼠进行CA/CPR。复苏后15分钟，小鼠接受静脉注射17β-雌二醇或赋形剂。CA后24小时完成血清化学检测和肾脏损伤的无偏立体学评估。通过激光多普勒测量局部肾皮质血流，并用免疫印迹法评估肾脏中雌激素受体α（ERα）和G蛋白偶联雌激素受体（GPER）的水平。
复苏后给予雌激素可减轻年轻雄性小鼠的损伤，而肾血流量无显著变化（与赋形剂相比降低的百分比：血清尿素氮，30%；血清肌酐（sCr），41%；坏死肾小管体积（VNT），31%；P < 0.05）。相比之下，雌激素对年轻雌性小鼠的任何结果均无影响。在老年小鼠中，雌激素显著降低了雄性小鼠的sCr（80%）和VNT（73%）以及雌性小鼠的VNT（51%）。CA/CPR后老年雌性小鼠的血清雌激素水平与雄性小鼠相同。随着年龄增长，雌性小鼠肾脏中的ERα上调。
CA复苏后给予雌激素可改善年轻雄性小鼠和老年两性小鼠的肾脏损伤。由于年轻雌性小鼠的损伤较小，未受影响。外源性雌激素的保护作用在老年雌性小鼠内源性雌激素丧失时可能可检测到，并且可能由肾脏ERs的差异介导。复苏后给予雌激素具有性别和年龄依赖性的肾脏保护作用。
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