Abstract: TH-OR061
PLK1 Inhibitor Can Reverse the Diabetic Nephropathy in OVE26 Type 1 Diabetic Mice
Session Information
- Diabetic Kidney Disease: Discovery of Molecular Mechanisms
November 07, 2019 | Location: 207, Walter E. Washington Convention Center
Abstract Time: 05:06 PM - 05:18 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Zhang, Lu, Icahn School of Medicine at Mount Sinai, Newyork, New York, United States
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, Newyork, New York, United States
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, Newyork, New York, United States
Background
Diabetic kidney disease (DKD) remains the leading cause of ESRD. However, treatment options are very limited. Since DKD is caused by multiple factors and its pathogenesis is complicated, it would be important to apply the systems biology to analyze the major gene signatures which are responsible for DKD and therefore, we could identify drugs which could reverse these gene signatures as potential treatment of DKD.
Methods
We analyzed all public transcriptomic dataset L1000CDS2 as a LINCS L1000 characteristic signature search engine has been applied widely in repurposing drugs for treatment of various diseases. Using this, we analyzed all public transcriptomic datasets related to DKD and GEO2Enrichr analysis to identify potential drugs, which reverse the gene signatures in DKD. We validated the findings by in vitro and in vivo studies.
Results
Gene expression datasets from 24 studies that compared DKD to normal kidney tissue were identified from GEO and Nephroseq. Differential expression was analyzed with GEO2Enrichr. We further performed meta-analysis of 27 DKD signatures from 24 studies using GEN3VA. Then L1000CDS2 was employed with each signature to prioritize matching above signatures created from over 20,000 drugs treatments of multiple human cell lines. We selected BI2536 from the top 5 most consistent drugs across the L1000CDS2 results, also considering their novelty and applications in other fields. BI2536 is a PLK1 inhibitor which can lead to cell cycle arrest and has been studied broadly in tumor treatments. We found PLK1 expression was increased in mouse glomeruli and localized mostly in mesangial cells. In vivo, we found that treatment of BI2536 attenuated albuminuria and renal histological changes, and expression of renal fibrosis and inflammation markers. We further compared the gene and pathways regulated in DKD but reversed by BI2536, which revealed Smad3 and NF-kB as the major pathways affected by BI2536. In vitro, we confirmed that BI2536 inhibited Smad3 and NF-kB phosphorylation in primary mesangial cells probably through direct interaction between PLK1 and these transcription factors.
Conclusion
Our data indicate that systems analysis could help to identify potential new drugs for treatment of DKD. BI2536 could be a potential drug which could reverse the gene signatures in DKD and the renal protective effect of BI2635 is validated in vivo animal model of DKD.
Funding
- NIDDK Support