Inhibition of MTOR Disrupts Autophagic Flux in Podocytes
Inhibition of MTOR Disrupts Autophagic Flux in Podocytes
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DOI：
10.1681/asn.2011070690
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发表时间：
2012-03-01
影响因子：
13.6
通讯作者：
Quaggin, Susan E.
中科院分区：
文献类型：
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作者：
Cina, Davide P.;Onay, Tuncer;Quaggin, Susan E.
雷帕霉素哺乳动物靶蛋白抑制剂（MTOR）属于具有强效免疫抑制、抗血管生成和抗增殖特性的药物家族。在这些药物治疗期间可能发生新发或恶化的蛋白尿，但其发生机制尚不清楚。我们产生并表征了携带足细胞选择性敲除Mtor基因的小鼠。虽然Mtor在发育中的足细胞中被抑制，但这些小鼠在出生后3周时出现蛋白尿，并在出生后5周时出现终末期肾衰竭。这些小鼠的足细胞显示自噬体标志物LC 3（大鼠微管相关蛋白1轻链3）、自噬体、自噬溶酶体囊泡和受损线粒体的积累。类似地，用MTOR抑制剂雷帕霉素处理的人足细胞积累自噬体和自噬溶酶体。总之，这些结果表明，自噬途径的破坏可能在用MTOR抑制剂治疗的患者中蛋白尿的发病机制中起作用。
Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubule-associated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.