基因敲除
肾
癌症研究
信号转导
疾病
体外
医学
肾脏疾病
细胞凋亡
生物
药理学
细胞生物学
内科学
遗传学
作者
Lu Zhang,Zichen Wang,Ruijie Liu,Zhengzhe Li,Jennifer Lin,Megan L. Wojciechowicz,Jian Huang,Kyung Hwa Lee,Avi Ma’ayan,John Cijiang He
出处
期刊:Diabetes
[American Diabetes Association]
日期:2020-10-16
卷期号:70 (2): 589-602
被引量:12
摘要
Diabetic kidney disease (DKD) remains the most common cause of kidney failure, and the treatment options are insufficient. Here, we used a connectivity mapping approach to first collect 15 gene expression signatures from 11 DKD-related published independent studies. Then, by querying the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 data set, we identified drugs and other bioactive small molecules that are predicted to reverse these gene signatures in the diabetic kidney. Among the top consensus candidates, we selected a PLK1 inhibitor (BI-2536) for further experimental validation. We found that PLK1 expression was increased in the glomeruli of both human and mouse diabetic kidneys and localized largely in mesangial cells. We also found that BI-2536 inhibited mesangial cell proliferation and extracellular matrix in vitro and ameliorated proteinuria and kidney injury in DKD mice. Further pathway analysis of the genes predicted to be reversed by the PLK1 inhibitor was of members of the TNF-α/NF-κB, JAK/STAT, and TGF-β/Smad3 pathways. In vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-κB and Smad3 signal transduction and transcriptional activation. Together, these results suggest that the PLK1 inhibitor BI-2536 should be further investigated as a novel therapy for DKD.
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