Improved renal ischemia tolerance in females influences kidney transplantation outcomes
Improved renal ischemia tolerance in females influences kidney transplantation outcomes
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DOI：
10.1172/jci84712
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发表时间：
2016-05-01
影响因子：
15.9
通讯作者：
Levine, Matthew H.
中科院分区：
文献类型：
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作者：
Aufhauser, David D., Jr.;Wang, Zhonglin;Levine, Matthew H.
在实验上，与男性相比，女性表现出更好的从缺血再灌注损伤(IRI)中恢复的能力；然而，这种性别依赖的反应在人类中较少确立。在这里，我们建立了一系列小鼠肾缺血和移植模型，以研究性别特异性对IRI后恢复的影响。我们发现，与雄性小鼠相比，雌性小鼠对IRI的耐受性大大增加，并在绝育后发现了一种中间的表型。将成人肾脏从任何性别移植到异性受者体内，然后在较远的时间进行缺血，导致缺血恢复，这反映了受者的性别，而不是供者的性别，这表明宿主性别决定恢复。同样，雌性雌激素受体α-KO小鼠肾脏IRI加重，而在缺血前补充雌激素的雌性小鼠受到保护。我们检查了来自器官共享联合网络(UNOS)的数据，以确定在接受已故供者肾移植的患者中，性别与移植延迟功能(DGF)之间是否存在关联。多变量Logistic回归分析表明，男性受者比女性受者与DGF的相关性更大。总之，我们的结果表明，性别影响小鼠和人类的肾脏IRI耐受性，并表明雌激素治疗有可能作为一种治疗干预措施，在临床上提高缺血耐受性。
Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor alpha-KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance.