Hypohalous Acids Contribute to Renal Extracellular Matrix Damage in Experimental Diabetes
Open accessAbstract
In diabetes, toxic oxidative pathways are triggered by persistent hyperglycemia and contribute to diabetes complications. A major proposed pathogenic mechanism is the accumulation of protein modifications that are called advanced glycation end products. However, other nonenzymatic post-translational modifications may also contribute to pathogenic protein damage in diabetes. We demonstrate that hypohalous acid–derived modifications of renal tissues and extracellular matrix (ECM) proteins are significantly elevated in experimental diabetic nephropathy. Moreover, diabetic renal ECM shows diminished binding of α1β1 integrin consistent with the modification of collagen IV by hypochlorous (HOCl) and hypobromous acids. Noncollagenous (NC1) hexamers, key connection modules of collagen IV networks, are modified via oxidation and chlorination of tryptophan and bromination of tyrosine residues. Chlorotryptophan, a relatively minor modification, has not been previously found in proteins. In the NC1 hexamers isolated from diabetic kidneys, levels of HOCl-derived oxidized and chlorinated tryptophan residues W28 and W192 are significantly elevated compared with nondiabetic controls. Molecular dynamics simulations predicted a more relaxed NC1 hexamer tertiary structure and diminished assembly competence in diabetes; this was confirmed using limited proteolysis and denaturation/refolding. Our results suggest that hypohalous acid–derived modifications of renal ECM, and specifically collagen IV networks, contribute to functional protein damage in diabetes.
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Nephrotoxicity and urogenital tract dysfunction are established pathological outcomes of chlorination stress.
“Nephrotoxity and urogenital tract dysfunction are established pathological outcomes of chlorination stress.”
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Acute kidney injury, glomerulonephritis, diabetic nephropathy, and bladder cancer have been associated with exposure to pathological chlorination stress.
“Among other pathologies, acute kidney injury, glomerulonephritis, diabetic nephropathy, and bladder cancer have been associated with exposure to pathological chlorination stress (110, 162–166).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [163]
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- Authors
- Brown, K. L., Darris, C., Rose, K. L., Sanchez, O. A., Madu, H., Avance, J., Brooks, N., Zhang, M.-Z., Fogo, A., Harris, R., Hudson, B. G., & Voziyan, P.
- Affiliations
- Vanderbilt University Medical Center (US)
- Berea College (US)
- Yale University (US)
- Corresponding author
- Voziyan, Paul
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2015-01-20
- Volume
- 64
- Issue
- 6
- Pages
- 2242-2253
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4439565
- OpenAlex
- W2102960454
- Cited by
- 62
- References
- 55
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 7 · 2020: 8 · 2019: 4 · 2018: 10 · 2017: 3 · 2016: 3 · 2015: 5
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- National Institutes of Health
- National Heart, Lung, and Blood Institute (5T-32HL-94296-06, T32HL094296)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK65123, R01DK051265, R37DK018381, T32DK007569, P01DK065123, DK-65138, R01DK056942, R01DK065138, DK-18381, R01DK018381, R01DK095785, R25DK096999)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- hypohalous acids, hypochlorous acid, hypobromous acid, diabetic nephropathy, renal extracellular matrix, type IV collagen, tryptophan oxidation, advanced glycation end products, post-translational modification, hyperglycemia, molecular dynamics simulation, limited proteolysis
- MeSH terms
- Animals, Bromates, Diabetes Mellitus, Experimental, Extracellular Matrix, Hypochlorous Acid, Kidney, Male, Integrins, Rats, Sprague-Dawley, Mice, Knockout, Mice, Rats, Nitric Oxide Synthase Type III, Molecular Dynamics Simulation
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