Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions
Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions
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DOI：
10.1073/pnas.1424313112
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发表时间：
2015-04-21
影响因子：
11.1
通讯作者：
Sparreboom, Alex
中科院分区：
文献类型：
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作者：
Pabla, Navjotsingh;Gibson, Alice A.;Sparreboom, Alex
急性肾损伤(AKI)是一种潜在的致命性综合征，其特征是肾小管细胞的缺血或毒性损伤导致肾功能迅速下降。广泛使用的化疗药物顺铂优先聚集在肾小管上皮细胞，是药物诱发急性肾损伤的常见原因。在AKI的发展过程中，静止的肾小管细胞重新进入细胞周期。阻断细胞周期进程的策略可能通过在存在广泛DNA损伤的情况下避免细胞分裂来改善肾脏损伤。然而，在AKI过程中导致细胞周期激活的早期信号事件尚不清楚。在目前的研究中，使用顺铂肾毒性的小鼠模型，我们证明了G1/S调节的细胞周期蛋白依赖性激酶4/6(CDK4/6)通路在肾细胞周期进入的同时被激活，但在急性肾损伤发生之前。小分子抑制剂帕波西利(PD-0332991)和核糖核酸库(LEE011)靶向抑制CDK4/6通路，可抑制细胞周期进程，改善肾脏损伤，提高总存活率。更重要的是，这些化合物被发现是有机阳离子转运蛋白2(OCT2)的有效抑制剂，OCT2有助于顺铂的细胞积累和随后的肾脏损伤。Palbociclib和LEE011独特的细胞周期和OCT2靶向活性，加上它们在临床翻译方面的潜力，支持进一步探索它们作为预防AKI的候选治疗药物。
Acute kidney injury (AKI) is a potentially fatal syndrome characterized by a rapid decline in kidney function caused by ischemic or toxic injury to renal tubular cells. The widely used chemotherapy drug cisplatin accumulates preferentially in the renal tubular cells and is a frequent cause of drug-induced AKI. During the development of AKI the quiescent tubular cells reenter the cell cycle. Strategies that block cell-cycle progression ameliorate kidney injury, possibly by averting cell division in the presence of extensive DNA damage. However, the early signaling events that lead to cell-cycle activation during AKI are not known. In the current study, usingmouse models of cisplatin nephrotoxicity, we show that the G1/S-regulating cyclin-dependent kinase 4/6 (CDK4/6) pathway is activated in parallel with renal cell-cycle entry but before the development of AKI. Targeted inhibition of CDK4/6 pathway by small-molecule inhibitors palbociclib (PD-0332991) and ribociclib (LEE011) resulted in inhibition of cell-cycle progression, amelioration of kidney injury, and improved overall survival. Of additional significance, these compounds were found to be potent inhibitors of organic cation transporter 2 (OCT2), which contributes to the cellular accumulation of cisplatin and subsequent kidney injury. The unique cell-cycle and OCT2-targeting activities of palbociclib and LEE011, combined with their potential for clinical translation, support their further exploration as therapeutic candidates for prevention of AKI.