title: Pyridoxamine protects proteins from damage by hypohalous acids in vitro and in vivo.
abstract: Diabetes is characterized, in part, by activation of toxic oxidative and glycoxidative pathways that are triggered by persistent hyperglycemia and contribute to diabetic complications. Inhibition of these pathways may benefit diabetic patients by delaying the onset of complications. One such inhibitor, pyridoxamine (PM), had shown promise in clinical trials. However, the mechanism of PM action in vivo is not well understood. We have previously reported that hypohalous acids can cause disruption of the structure and function of renal collagen IV in experimental diabetes (K.L. Brown et al., Diabetes 64:2242-2253, 2015). In the present study, we demonstrate that PM can protect protein functionality from hypochlorous and hypobromous acid-derived damage via a rapid direct reaction with and detoxification of these hypohalous acids. We further demonstrate that PM treatment can ameliorate specific hypohalous acid-derived structural and functional damage to the renal collagen IV network in a diabetic animal model. These findings suggest a new mechanism of PM action in diabetes, namely sequestration of hypohalous acids, which may contribute to known therapeutic effects of PM in human diabetic nephropathy.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Hartman
authors.initials: H
authors.lastname: Madu
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Avance
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Chetyrkin
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Darris
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Kristie Lindsey
authors.initials: KL
authors.lastname: Rose
authors.affiliation: Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Otto A
authors.initials: OA
authors.lastname: Sanchez
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Billy
authors.initials: B
authors.lastname: Hudson
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: paul.voziyan@vanderbilt.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Voziyan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001959:Bromates / Q000633:toxicity; D002853:Chromatography, Liquid; D024141:Collagen Type IV / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D006997:Hypochlorous Acid / Q000633:toxicity*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D016877:Oxidants / Q000633:toxicity; D010084:Oxidation-Reduction; D059748:Proteolysis / Q000187:drug effects*; D011733:Pyridoxamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D014803:Vitamin B Complex / Q000494:pharmacology*
chemical_list: D001959:Bromates; D024141:Collagen Type IV; D016877:Oxidants; D014803:Vitamin B Complex; D011733:Pyridoxamine; D006997:Hypochlorous Acid; C027664:hypobromous acid
keywords: Diabetes; Free radicals; Hypobromous acid; Hypochlorous acid; Nephropathy; Posttranslational modifications; Protein halogenation; Pyridoxamine