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Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome

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Abstract

Purpose

The current study aims to determine the molecular mechanisms of diabetic retinopathy (DR) using the protein-protein interactome and metabolome map. We examined the protein network of novel biomarkers of DR for direct (physical) and indirect (functional) interactions using clinical target proteins in different models.

Methods

We used proteomic tools including 2-dimensional gel electrophoresis, mass spectrometry analysis, and database search for biomarker identification using in vivo murine and human model of diabetic retinopathy and in vitro model of oxidative stress. For the protein interactome and metabolome mapping, various bioinformatic tools that include STRING and OmicsNet were used.

Results

We uncovered new diabetic biomarkers including prohibitin (PHB), dynamin 1, microtubule-actin crosslinking factor 1, Toll-like receptor (TLR 7), complement activation, as well as hypothetical proteins that include a disintegrin and metalloproteinase (ADAM18), vimentin III, and calcium-binding C2 domain-containing phospholipid-binding switch (CAC2PBS) using a proteomic approach. Proteome networks of protein interactions with diabetic biomarkers were established using known DR-related proteome data. DR metabolites were interconnected to establish the metabolome map. Our results showed that mitochondrial protein interactions were changed during hyperglycemic conditions in the streptozotocin-treated murine model and diabetic human tissue.

Conclusions

Our interactome mapping suggests that mitochondrial dysfunction could be tightly linked to various phases of DR pathogenesis including altered visual cycle, cytoskeletal remodeling, altered lipid concentration, inflammation, PHB depletion, tubulin phosphorylation, and altered energy metabolism. The protein-metabolite interactions in the current network demonstrate the etiology of retinal degeneration and suggest the potential therapeutic approach to treat DR.

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Funding

The current research was supported in part by Research Assistantship and Teaching Assistantship from the American University of Nigeria.

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Authors and Affiliations

  1. Retina Proteomics Laboratory, Department of Petroleum Chemistry, American University of Nigeria, Yola, Nigeria

    Ambrose Teru Patrick, Joshua Madu, Faith Pwaniyibo Samson & Wan Jin Jahng

  2. Department of Biomedical Engineering, Michigan Technological University, Houghton, MI, USA

    Weilue He

  3. Department of Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Srinivas R. Sripathi

  4. Division of Vitreous and Retina, Department of Ophthalmology, College of Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, Korea

    Seulggie Choi, Kook Lee & Donghyun Jee

  5. Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA

    Folami L. Powell

  6. Department of Ophthalmology, Augusta University, Augusta, GA, USA

    Manuela Bartoli & Diana R. Gutsaeva

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  1. Ambrose Teru Patrick
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Correspondence to Wan Jin Jahng.

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ESM 1

Dissection of the retina control map showing several pathways, including PI3K, WNT, cytoskeleton, apoptosis, p53, VEGF, HIF-1, and cholesterol mechanism. A. PI3K-AKT signaling, B. WNT network, C. Actin cytoskeletal network, D. Apoptosis, E. p53 network, F. VEGF pathway, G. HIF-1 network, H. Cholesterol metabolism. (PDF 5027 kb)

ESM 2

Mechanistic dissection of the interactome network leading to the pathogenesis of diabetic retinopathy, A. Apoptosis, B. Angiogenesis, C. Inflammation network, D. Retinoid metabolism, E. Vascular permeability/occlusion, F. Energy metabolism network, G. Lipid metabolism, H. Cytoskeleton organization, I. Mitochondria dysfunction, J. Hyperglycemia, K. Oxidative stress. (PDF 7678 kb)

ESM 3

Identified proteins in the retina as the control. A total of 1090 proteins were identified as biological, cellular, and molecular functional proteins which serve as the control proteins in the retina. Control interactome map was established using bioinformatics tools including PPI software STRING (http://string-db.org/) by adding 1104 identified normal eye proteins in the query. (XLSX 111 kb)

ESM 4

DR biomarkers. DR-specific proteins were identified from our proteomics study, protein database, and proteomics literature. These proteins were considered DR biomarkers and used in bioinformatics analysis. DR-specific interactome map was established using STRING to find the probable interacting partners of the proteins associated with DR. These potential DR biomarkers are presented in the interaction map and mechanistic dissection was presented in Supplement Figures 2A-2K. (XLSX 35 kb)

ESM 5

Metabolites associated with DR pathogenesis. A total of 121 metabolites were collected from the literature and databases including KEGG and PubChem. The metabolome map was established using bioinformatics tools including OmicsNet software by adding 121 metabolites in the query. (XLSX 19 kb)

ESM 6

Reverse interactome mapping from the metabolome map. A total of 115 proteins related to DR were identified as the DR-specific metabolome-proteome interactions from the nodes of metabolites in the metabolome map. Proteins obtained from the metabolome-proteome interactions were added in STRING software and determined the protein interactions. (XLSX 14 kb)

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Patrick, A.T., He, W., Madu, J. et al. Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome. J Diabetes Metab Disord 19, 829–848 (2020). https://doi.org/10.1007/s40200-020-00570-9

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  • DOI: https://doi.org/10.1007/s40200-020-00570-9

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