AKT2 is essential to maintain podocyte viability and function during chronic kidney disease
AKT2 is essential to maintain podocyte viability and function during chronic kidney disease
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DOI：
10.1038/nm.3313
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发表时间：
2013-10-01
期刊：
影响因子：
82.9
通讯作者：
Terzi, Fabiola
中科院分区：
文献类型：
--
作者：
Canaud, Guillaume;Bienaime, Frank;Terzi, Fabiola
在慢性肾脏病 (CKD) 中，功能性肾单位的丧失会导致剩余肾单位的代谢和机械应激，从而导致肾单位进一步丧失。在这里，我们表明 Akt2 激活在肾单位减少后的足细胞保护中具有重要作用。与野生型小鼠相比，Akt2(-/-) 小鼠的肾小球硬化和蛋白尿明显恶化，而 Akt1(-/-) 小鼠则没有。足细胞中 Akt2 或其调节因子 Rictor 的特异性缺失揭示了 Akt2 在足细胞中具有内在功能。从机制上讲，Akt2 触发一个涉及小鼠双分钟 2 同源物 (Mdm2)、糖原合酶激酶 3 (Gsk3) 和 Rac1 的补偿程序。肾单位减少后该途径的激活缺陷导致足细胞凋亡和足突消失。我们进一步表明，哺乳动物雷帕霉素靶标复合物 2 (mTORC2) 激活 AKT2 对于人类 CKD 足细胞的存活也是必需的。更值得注意的是，我们阐明了西罗莫司肾不良反应的潜在事件，并为合理使用该药物提供了标准。因此，我们的结果揭示了 Akt2 的新功能，并确定了保留 CKD 肾小球功能的潜在治疗靶点。
In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.