Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5T 3L9 Canada.
J Am Soc Nephrol. 2012 Mar;23(3):412-20. doi: 10.1681/ASN.2011070690. Epub 2011 Dec 22.
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.
哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂属于具有强大免疫抑制、抗血管生成和抗增殖作用的药物家族。在使用这些药物治疗期间，可能会发生新的或恶化的蛋白尿，但发生这种情况的机制尚不清楚。我们生成并鉴定了一种在足细胞中选择性敲除 Mtor 基因的小鼠。尽管 Mtor 在发育中的足细胞中是可有可无的，但这些小鼠在出生后 3 周时出现蛋白尿，在 5 周时发展为终末期肾衰竭。这些小鼠的足细胞中出现了自噬体标志物 LC3（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的线粒体的积累。同样，用 mTOR 抑制剂雷帕霉素处理的人足细胞也积累了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接受 mTOR 抑制剂治疗的患者的蛋白尿发病机制中起作用。
