Connectivity Mapping Identifies BI-2536 as a Potential Drug to Treat Diabetic Kidney Disease

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 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.

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Connectivity mapping identifies BI-2536 as a potential drug to treat diabetic kidney disease

10.2337/figshare.13061864 ◽

2020 ◽

Author(s):

Ada Admin ◽

Lu Zhang ◽

Zichen Wang ◽

Ruijie Liu ◽

Zhengzhe Li ◽

...

Keyword(s):

Kidney Disease ◽

Transcriptional Activation ◽

Diabetic Kidney Disease ◽

Mesangial Cells ◽

Novel Therapy ◽

Integrated Network ◽

Diabetic Kidney ◽

Connectivity Mapping ◽

Bi 2536

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 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.

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Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease

Scientific Reports ◽

10.1038/s41598-020-71950-7 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Julie Klein ◽

Cécile Caubet ◽

Mylène Camus ◽

Manousos Makridakis ◽

Colette Denis ◽

...

Keyword(s):

Kidney Disease ◽

Large Scale ◽

Diabetic Kidney Disease ◽

Enzyme Inhibitor ◽

Oral Treatment ◽

Drug Repurposing ◽

Water Soluble ◽

Diabetic Patients ◽

Diabetic Kidney ◽

Connectivity Mapping

Abstract While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25–30% of diabetic patients still develop the disease. In the present work we adopted a systems biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic (Ins2Akita) mice treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). The raw data are publicly available via ProteomeXchange with identifier PXD018728. We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthenolide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Oral treatment of 2 months old Ins2Akita mice with dimethylaminoparthenolide (DMAPT, a water-soluble analogue of parthenolide) for two months at 10 mg/kg/d by gavage significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach, we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.

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