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., Diabetes64:2242-2253, 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.
|Original language||English (US)|
|Number of pages||8|
|Journal||Free Radical Biology and Medicine|
|State||Published - Dec 1 2015|
Bibliographical noteFunding Information:
The authors thank Ms. Parvin Todd and Ms. Salisha Hill for expert technical help and Dr. Vadim Pedchenko for helpful discussions. This work was supported by Grant DK65138 from the National Institutes of Health . Mr. Hartman Madu was supported by Summer Student Research Grant DK65123 from the National Institutes of Health. Dr. Carl Darris was supported by Research Fellowship Award T32DK007569-24S from the National Institutes of Health. Mr. Josh Avance was supported by the Vanderbilt Aspirnaut Program and 1R25DK096999 and NIDDKD Step-Up grants from the National Institutes of Health.
- Hypobromous acid
- Hypochlorous acid
- Posttranslational modifications
- Protein halogenation