Hypohalous acids contribute to renal extracellular matrix damage in experimental diabetes.

Brown KL, Darris C, Rose KL, Sanchez OA, Madu H, Avance J, Brooks N, Zhang MZ, Fogo A, Harris R, Hudson BG, Voziyan P
Diabetes. 2015 64 (6): 2242-53

PMID: 25605804 · PMCID: PMC4439565 · DOI:10.2337/db14-1001

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 W(28) and W(192) 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.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

MeSH Terms (14)

Animals Bromates Diabetes Mellitus, Experimental Extracellular Matrix Hypochlorous Acid Integrins Kidney Male Mice Mice, Knockout Molecular Dynamics Simulation Nitric Oxide Synthase Type III Rats Rats, Sprague-Dawley

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