Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner.
Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner.
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DOI：
10.1186/s13054-015-1049-8
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发表时间：
2015-09-18
期刊：
影响因子：
--
通讯作者：
Hutchens MP
中科院分区：
文献类型：
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作者：
Ikeda M;Swide T;Vayl A;Lahm T;Anderson S;Hutchens MP
缺血性急性肾损伤（阿基）的风险存在性别差异，雌激素介导了女性的保护作用。我们先前证明，卵巢切除雌性小鼠的生理性雌激素的术前慢性恢复改善了心脏骤停和心肺复苏（CA/CPR）后的阿基。在本研究中，我们假设雄性小鼠和老年雌性小鼠将受益于CA/CPR后的雌激素给药。我们通过在CA/CPR后给予雌激素，以临床相关的方式测试了雌激素的作用。在年轻（10-15周）、中年（43-48周）和老年（78-87周）C57 BL/6雄性和雌性小鼠中进行CA/CPR。小鼠在复苏后15分钟静脉注射17β-雌二醇或溶媒。CA后24小时完成血清化学和肾损伤的无偏倚体视学评估。通过激光多普勒测量局部肾皮质血流量，并通过免疫印迹评估肾脏雌激素受体α（ERα）和G蛋白偶联雌激素受体（GPER）的水平。停搏后给予雌激素减少了年轻男性的损伤，而肾血流没有显著变化（与载体相比减少百分比：血清尿素氮，30%;血清肌酐（sCr），41%;坏死小管体积（VNT），31%; P < 0.05）。相反，雌激素对年轻女性的任何结果都没有影响。在老年小鼠中，雌激素显著降低雄性sCr（80%）和VNT（73%）以及雌性VNT（51%）。CA/CPR后老年雌性小鼠血清雌激素水平与雄性小鼠相同。随着年龄的增长，女性肾脏ERα表达上调。CA复苏后给予雌激素可改善年轻雄性和老年雄性小鼠的肾损伤。由于损伤较小，年轻女性未受影响。外源性雌激素的保护作用可能与老年女性内源性雌激素的丢失有关，并可能通过肾脏ER的差异介导。停搏后给予雌激素具有性别和年龄依赖性的肾脏保护作用。
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.