Hypohalous acids contribute to renal extracellular matrix damage in experimental diabetes.
Hypohalous acids contribute to renal extracellular matrix damage in experimental diabetes.
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作者：
Brown KL;Darris C;Rose KL;Sanchez OA;Madu H;Avance J;Brooks N;Zhang MZ;Fogo A;Harris R;Hudson BG;Voziyan P
在糖尿病中，毒性氧化途径由持续高血糖症触发，并导致糖尿病并发症。一个主要的致病机制是蛋白质修饰的积累，称为晚期糖基化终产物。然而，其他非酶翻译后修饰也可能导致糖尿病中的致病性蛋白质损伤。我们证明，在实验性糖尿病肾病中，肾组织和细胞外基质（ECM）蛋白的次卤酸衍生修饰显著升高。此外，糖尿病肾ECM显示α1β1整联蛋白结合减少，这与次氯酸（HOCl）和次溴酸对胶原IV的修饰一致。非胶原（NC 1）六聚体，胶原蛋白IV网络的关键连接模块，通过氧化和氯化色氨酸和溴化酪氨酸残基进行修饰。氯色氨酸是一种相对较小的修饰，以前在蛋白质中没有发现。在NC 1六聚体分离糖尿病肾脏，HOCl衍生的氧化和氯化色氨酸残基W28和W192的水平显着升高相比，非糖尿病对照。分子动力学模拟预测更宽松的NC 1六聚体的三级结构和减少装配能力在糖尿病，这是证实了有限的蛋白水解和变性/重折叠。我们的研究结果表明，次卤酸衍生的肾ECM的修改，特别是胶原蛋白IV网络，有助于糖尿病的功能蛋白质损伤。
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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影响因子：
6.8
作者：
Hermo, R;Mier, C;Gugliucci, AG
通讯作者：
Gugliucci, AG
DOI：
10.1196/annals.1333.061
发表时间：
2005-01-01
期刊：
MAILLARD REACTION: CHEMISTRY AT THE INTERFACE OF NUTRITION, AGING, AND DISEASE
影响因子：
--
作者：
Monnier, VM;Mustata, GT;Sell, DR
通讯作者：
Sell, DR
DOI：
10.1016/j.bbagen.2013.05.024
发表时间：
2013-10-01
影响因子：
3
作者：
Kubala, Lukas;Kolarova, Hana;Eiserich, Jason P.
通讯作者：
Eiserich, Jason P.
影响因子：
7.7
作者：
Baynes, JW;Thorpe, SR
通讯作者：
Thorpe, SR
影响因子：
7.4
作者：
Kato, Y;Kawai, Y;Osawa, T
通讯作者：
Osawa, T