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Connectivity mapping identifies BI-2536 as a potential drug to treat diabetic kidney disease
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posted on 2020-10-16, 21:52 authored by Ada AdminAda Admin, Lu Zhang, Zichen Wang, Ruijie Liu, Zhengzhe Li, Jennifer Lin, Megan L. Wojciechowicz, Jiyi Huang, Kyung Lee, Avi Ma’ayan, John Cijiang HeDiabetic
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 dataset, 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 were of members of
the TNF-α/NF-kB, JAK/STAT, and TGF-β/Smad3 pathways. In
vitro, either BI-2536 treatment or knockdown of PLK1 dampened the NF-kB 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.