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

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.

Applying Proteomics and Integrative “Omics” Strategies to Decipher the Chronic Kidney Disease-Related Atherosclerosis

“…The pathological link between diabetes and atherosclerosis is also well-documented by others [ 126 ]. While the large number of proteomic or even multiomics investigations of diabetic kidney disease (DKD) have been presented, our knowledge about these mechanisms is limited [ 127 , 128 , 129 ]. This is mainly because diabetes is linked also with a variety of other comorbidities.…”

Proteomic analysis of mouse kidney tissue associates peroxisomal dysfunction with early diabetic kidney disease

“…The mouse models C57BL/6-Ins2Akita/J (Ins2Akita-T1D) and BKS.Cg-+Leprdb/+Leprdb/OlaHsd (dbdb-T2D) were used. In the glomerular proteome study 4 groups of animals were included, 2month-old Ins2Akita (INS2) (n=8) and respective controls (WT2; n=7); and 4-month-old Ins2Akita (INS4) (n=8) and respective controls (WT4, n=8) (7). For the kidney cortex proteome study db/db mice were used.…”

“…Glomeruli were isolated as previously described in (7) Klein J, et al 2020. In brief, mice were anesthetized and a catheter was placed into the abdominal aorta.…”

“…Kidney histology was performed as described in (7) Klein J, et al 2020. In brief, kidney lesions were assessed by specific (immuno) histological evaluation of the kidney structure (PAS) and fibrosis (glomerulo and tubulointerstitial fibrosis, Masson-trichrome and Sirius red staining, collagen III staining).…”

“…DKD is characterized by kidney ultra-structural and morphological alterations such as mesangial expansion, nodular glomerular sclerosis, glomerular basement membrane (GBM) thickening, and tubulointerstitial fibrosis (6). Glomerular injury characterizes the early stages of DKD, thus glomeruli are significant targets to investigate the molecular mechanisms of early DKD pathogenesis (7).…”