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Abstract：
Podocyte loss in glomeruli is a fundamental event in the pathogenesis of chronic kidney diseases. Currently, mitotic catastrophe (MC) has emerged as the main cause of podocyte loss. However, the regulation of MC in podocytes has yet to be elucidated. The current work aimed to study the role and mechanism of p53 in regulating the MC of podocytes using adriamycin (ADR)-induced nephropathy. In vitro podocyte stimulation with ADR triggered the occurrence of MC, which was accompanied by hyperactivation of p53 and cyclin-dependent kinase (CDK1)/cyclin B1. The inhibition of p53 reversed ADR-evoked MC in podocytes and protected against podocyte injury and loss. Further investigation showed that p53 mediated the activation of CDK1/cyclin B1 by regulating the expression of Wee1. Restraining Wee1 abolished the regulatory effect of p53 inhibition on CDK1/cyclin B1 and rebooted MC in ADR-stimulated podocytes via p53 inhibition. In a mouse model of ADR nephropathy, the inhibition of p53 ameliorated proteinuria and podocyte injury. Moreover, the inhibition of p53 blocked the progression of MC in podocytes in ADR nephropathy mice through the regulation of the Wee1/CDK1/cyclin B1 axis. Our findings confirm that p53 contributes to MC in podocytes through regulation of the Wee1/CDK1/Cyclin B1 axis, which may represent a novel mechanism underlying podocyte injury and loss during the progression of chronic kidney disorder.
摘要：
肾小球足细胞丢失是慢性肾脏病发病机制中的基本事件。目前,有丝分裂突变（MC）已成为足细胞损失的主要原因。然而,足细胞中MC的调节尚未阐明。本研究旨在研究p53在阿霉素（ADR）诱导的肾病足细胞MC中的作用及其机制。体外足细胞刺激与ADR引发MC的发生，伴有p53和细胞周期蛋白依赖性激酶（CDK1）/细胞周期蛋白B1的过度激活。p53的抑制逆转了足细胞中ADR诱发的MC，并防止了足细胞的损伤和损失。进一步研究表明，p53通过调节Wee1的表达介导CDK1/cyclinB1的激活。抑制Wee1消除了p53抑制对CDK1/cyclinB1的调节作用，并通过p53抑制在ADR刺激的足细胞中重新启动MC。在ADR肾病的小鼠模型中，抑制p53可改善蛋白尿和足细胞损伤。此外，p53的抑制通过调节Wee1/CDK1/cyclinB1轴阻断ADR肾病小鼠足细胞中MC的进展。我们的发现证实，p53通过调节Wee1/CDK1/CyclinB1轴促进足细胞中的MC，这可能代表了慢性肾脏疾病进展过程中足细胞损伤和丢失的新机制。
