Cdk5-Mediated Phosphorylation of Sirt1 Contributes to Podocyte Mitochondrial Dysfunction in Diabetic Nephropathy
Cdk5-Mediated Phosphorylation of Sirt1 Contributes to Podocyte Mitochondrial Dysfunction in Diabetic Nephropathy
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Cdk5 介导的 Sirt1 磷酸化导致糖尿病肾病足细胞线粒体功能障碍
DOI：
10.1089/ars.2020.8038
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发表时间：
2020-08-12
影响因子：
6.6
通讯作者：
Duan, Huijun
中科院分区：
文献类型：
--
作者：
Wang, Shuo;Yang, Yakun;Duan, Huijun
目的：线粒体功能障碍导致足细胞损伤，足细胞损伤是糖尿病肾病（DN）蛋白尿的主要原因。在这项研究中，我们探讨了细胞周期蛋白依赖性激酶5（Cdk 5）在糖尿病条件下足细胞线粒体功能障碍的作用。结果：糖尿病状态下，Cdk 5在体内和体外的表达和活性均显著上调，同时伴有突触足蛋白和nephrin的下调，以及线粒体结构和功能的异常。用roscovitine或显性负性Cdk 5抑制Cdk 5通过上调synaptopodin和nephrin导致足细胞损伤的减弱。Cdk 5的抑制还通过降低活性氧水平和细胞色素c释放而改善线粒体功能障碍，同时增加三磷酸腺苷的产生。Sirt 1是一种NAD（+）依赖性脱乙酰酶，在高糖（HG）处理的足细胞中减少;然而，其在S47的磷酸化水平显著上调。我们证明，HG水平导致过度活跃的Cdk 5磷酸化Sirt 1在S47。在体内和体外实验中，Cdk 5的抑制降低了Sirt 1磷酸化水平和S47突变为不可磷酸化的丙氨酸（S47 A），显著减轻了糖尿病条件下足细胞损伤和线粒体功能障碍。创新与结论：我们的研究表明Cdk 5通过Sirt 1磷酸化调节线粒体功能，因此可能成为DN治疗的新靶点。IRB编号：20190040。
Aims:Mitochondrial dysfunction contributes to podocyte injury, which is the leading cause of proteinuria in diabetic nephropathy (DN). In this study, we explored the role of cyclin-dependent kinase 5 (Cdk5) in mitochondrial dysfunction of podocytes under diabetic conditions. Results:Our results showed that the expression and activity of Cdk5 were significantly upregulatedin vivoandin vitrounder diabetic conditions, accompanied by the downregulation of synaptopodin and nephrin, as well as structural and functional mitochondrial dysfunction. Inhibition of Cdk5 with roscovitine or dominant-negative Cdk5 led to the attenuation of podocyte injury by upregulating synaptopodin and nephrin. The inhibition of Cdk5 also ameliorated mitochondrial dysfunction by decreasing reactive oxygen species levels and cytochrome c release, while increasing adenosine triphosphate production. Sirt1, an NAD(+)-dependent deacetylase, was decreased in podocytes with high glucose (HG) treatment; however, its phosphorylation level at S47 was significantly upregulated. We demonstrated that HG levels cause overactive Cdk5 to phosphorylate Sirt1 at S47. Suppression of Cdk5 reduced Sirt1 phosphorylation levels and mutation of S47 to nonphosphorable alanine (S47A), significantly attenuated podocyte injury and mitochondrial dysfunction in diabetic conditionin vivoandin vitro. Innovation and Conclusion:Our study has demonstrated the role of Cdk5 in regulating mitochondrial function through Sirt1 phosphorylation and thus can potentially be a new therapeutic target for DN treatment. IRB number: 20190040.