Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Vanderbilt Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, TN, 37212, USA.
Department of Biochemistry, Vanderbilt University, Nashville, TN, 37232, USA.
Biochem Biophys Res Commun. 2023 Dec 31;689:149237. doi: 10.1016/j.bbrc.2023.149237. Epub 2023 Nov 11.
Diabetic complications present a serious health problem. Functional damage to proteins due to post-translational modifications by glycoxidation reactions is a known factor contributing to pathology. Extracellular proteins are especially vulnerable to diabetic damage because robust antioxidant defenses are lacking outside the cell. We investigated glucose-induced inactivation of peroxidasin (PXDN), a heme protein catalyzing sulfilimine crosslinking of collagen IV that reinforce the basement membranes (BM). Experiments using physiological diabetic glucose levels were carried out to exclude several potential mechanisms of PXDN inactivation i.e., direct adduction of glucose, reactive carbonyl damage, steric hindrance, and osmotic stress. Further experiments established that PXDN activity was inhibited via heme degradation by reactive oxygen species. Activity of another extracellular heme protein, myeloperoxidase, was unaffected by glucose because its heme was resistant to glucose-induced oxidative degradation. Our findings point to specific mechanisms which may compromise BM structure and stability in diabetes and suggest potential modes of protection.
糖尿病并发症是一个严重的健康问题。由于糖基化反应引起的翻译后修饰导致蛋白质功能受损，这是导致病理学的已知因素。细胞外蛋白质特别容易受到糖尿病的损害，因为细胞外缺乏强大的抗氧化防御。我们研究了葡萄糖诱导的过氧化物酶（PXDN）失活，PXDN 是一种催化 IV 型胶原磺基赖氨酸交联的血红素蛋白，可增强基底膜（BM）。使用生理糖尿病葡萄糖水平进行的实验排除了 PXDN 失活的几种潜在机制，即葡萄糖的直接加成、反应羰基损伤、空间位阻和渗透压应激。进一步的实验表明，活性氧物种通过血红素降解抑制 PXDN 活性。另一种细胞外血红素蛋白髓过氧化物酶的活性不受葡萄糖影响，因为其血红素不易受到葡萄糖诱导的氧化降解。我们的发现指出了可能损害糖尿病中 BM 结构和稳定性的特定机制，并提出了潜在的保护模式。
