PACS2/PKCα/NOX4 pathway damaged the renal vascular endothelial barrier by promoting ROS production in diabetic nephropathy mice.

IF 3.7 2区 生物学 Q3 CELL BIOLOGY
Xinru Zheng, Qianjun Zhu, Jie Ouyang, Jing Zhang, Quanjun Liu, Jianing Fan, Peng Gao, Haijiao Long, Hong Xiang, Hongwei Lu
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Abstract

Renal vascular endothelial barrier dysfunction plays an important role in the pathogenesis of diabetic nephropathy (DN). Reactive oxygen species (ROS) contribute to barrier dysfunction in various aspects of diabetes. Phosphofurin acidic cluster sorting protein 2 (PACS2) is related to the ROS production, but the specific signaling pathway in endothelial cells remains unclear. In this study, we explored the mechanistic function of PACS2 and its downstream PKCα/NOX4 signaling pathway in endothelial barrier damage in DN. A significant upregulation of PACS2 expression was observed in human umbilical vein endothelial cells treated with high glucose and palmitic acid and glomerular endothelial cells derived from STZ + HFD-induced DN mice. SiRNA-mediated silencing or knockdown of PACS2 reversed the impaired vascular barrier function in vivo and in vitro. Furthermore, the inhibition of PACS2 significantly downregulated the protein expression of PKCα and NOX4 protein and the production of ROS in endothelial cells. Collectively, our findings indicate that the PACS2/PKCα/NOX4 signaling pathway may participate in the pathogenesis of DN by regulating vascular endothelial barrier function.

PACS2/PKCα/NOX4通路通过促进糖尿病肾病小鼠ROS的产生破坏肾血管内皮屏障。
肾血管内皮屏障功能障碍在糖尿病肾病(DN)的发病机制中起重要作用。活性氧(ROS)在糖尿病的各个方面都有助于屏障功能障碍。磷酸氟酸簇分选蛋白2 (Phosphofurin acid cluster sorting protein 2, PACS2)与ROS的产生有关,但其在内皮细胞中的具体信号通路尚不清楚。在本研究中,我们探讨了PACS2及其下游PKCα/NOX4信号通路在DN内皮屏障损伤中的机制作用。在高糖和棕榈酸处理的人脐静脉内皮细胞和STZ + hfd诱导的DN小鼠肾小球内皮细胞中,PACS2的表达显著上调。在体内和体外,sirna介导的PACS2沉默或敲低逆转了受损的血管屏障功能。此外,抑制PACS2可显著下调内皮细胞中PKCα和NOX4蛋白的表达以及ROS的产生。总之,我们的研究结果表明,PACS2/PKCα/NOX4信号通路可能通过调节血管内皮屏障功能参与DN的发病过程。
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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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