While epidemiological and experimental studies have demonstrated kidney-protective effects of estrogen and female sex in adulthood, some epidemiological data showed deterioration of kidney function during puberty when estrogen production increases. However, molecular mechanisms explaining these conflicting phenomena remain unknown. Here, we showed that the pubertal sex hormone surge in female mice increases susceptibility to kidney ischemia reperfusion injury partly via downregulation of insulin-like growth factor 1 receptor (IGF-1R) expression in proximal tubules. Adult mice ovariectomized pre-pubertally (at postnatal day 21) showed strong tolerance to kidney ischemia, which was partly reversed by the administration of 17β-estradiol, while adult mice ovariectomized post-pubertally (at 8 weeks of age) were vulnerable to kidney ischemia. Kidney tubular IGF-1R protein expression decreased during postnatal growth but was highly expressed in adult mice ovariectomized pre-pubertally and in infant mice, which might be partly explained by different expression of an E3 ligase (MDM2) of IGF-1R. Mice deficient of Igf-1r in proximal tubules (iIGF-1RKO mice) during postnatal kidney growth showed increased susceptibility to ischemic injury. RNA-seq and western blotting analysis using proximal tubular cells from pre-pubertally ovariectomized iIGF-1RKO and control mice revealed altered expression of cell cycle-associated molecules such as cyclin D1. These results suggest that Igf-1r deletion during postnatal growth renders proximal tubular cells susceptible to ischemia possibly via altered cell cycle regulation. Thus, our findings provide evidence that exposure to pubertal sex hormones leads to increased susceptibility to kidney ischemia, which is partly mediated by modulation of IGF-1R signaling.

中文翻译：

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女性性激素在一生中对急性肾病易感性产生反向调节。


虽然流行病学和实验研究表明，雌激素和女性在成年期具有肾脏保护作用，但一些流行病学数据显示，当雌激素产生增加时，青春期肾功能会恶化。然而，解释这些冲突现象的分子机制仍然未知。在这里，我们表明雌性小鼠青春期性激素激增增加了对肾缺血再灌注损伤的易感性，部分是通过下调近端肾小管中胰岛素样生长因子 1 受体 （IGF-1R） 的表达。青春期前 （出生后第 21 天） 切除卵巢的成年小鼠对肾缺血表现出很强的耐受性，这部分被 17β-雌二醇的施用逆转，而青春期后 （8 周龄） 去卵巢的成年小鼠易患肾缺血。肾小管 IGF-1R 蛋白表达在出生后生长过程中降低，但在青春期前切除卵巢的成年小鼠和婴儿小鼠中高度表达，这可能部分是由于 IGF-1R 的 E3 连接酶 （MDM2） 表达不同。在出生后肾脏生长过程中，近端小管缺乏 Igf-1r 的小鼠 （iIGF-1RKO 小鼠） 表现出对缺血性损伤的易感性增加。使用来自青春期前卵巢切除 iIGF-1RKO 和对照小鼠的近端肾小管细胞的 RNA-seq 和 western blotting 分析显示细胞周期相关分子（如细胞周期蛋白 D1）的表达发生改变。这些结果表明，出生后生长过程中 Igf-1r 缺失使近端肾小管细胞易发生缺血，这可能是由于细胞周期调节改变。 因此，我们的研究结果提供了证据，表明暴露于青春期性激素会导致对肾缺血的易感性增加，这部分是由 IGF-1R 信号传导的调节介导的。