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Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease
Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease
- Source :
- Scientific Reports, Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.14898. ⟨10.1038/s41598-020-71950-7⟩, Scientific Reports, 2020, 10 (1), pp.14898. ⟨10.1038/s41598-020-71950-7⟩, Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
Abstract
- International audience; 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.
- Subjects :
- Proteomics
Male
[SDV]Life Sciences [q-bio]
Kidney Glomerulus
lcsh:Medicine
Angiotensin-Converting Enzyme Inhibitors
Diabetic nephropathy
Article
Renin-Angiotensin System
Angiotensin Receptor Antagonists
Mice
Chronic kidney disease
Connectome
Animals
Diabetic Nephropathies
lcsh:Science
Kidney diseases
Drug discovery
lcsh:R
Diagnostic markers
Computational biology and bioinformatics
[SDV] Life Sciences [q-bio]
Mice, Inbred C57BL
Diabetes Mellitus, Type 1
Gene Expression Regulation
Nephrology
lcsh:Q
Sesquiterpenes
Biomarkers
Glomerular Filtration Rate
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Database :
- OpenAIRE
- Journal :
- Scientific Reports, Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.14898. ⟨10.1038/s41598-020-71950-7⟩, Scientific Reports, 2020, 10 (1), pp.14898. ⟨10.1038/s41598-020-71950-7⟩, Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
- Accession number :
- edsair.pmid.dedup....ed44fa7306659132bfb73167665602c8
- Full Text :
- https://doi.org/10.1038/s41598-020-71950-7⟩