Alterations in nonenzymatic biochemistry in uremia: Origin and significance of "carbonyl stress" in long-term uremic complications
Alterations in nonenzymatic biochemistry in uremia: Origin and significance of "carbonyl stress" in long-term uremic complications
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DOI：
10.1046/j.1523-1755.1999.00302.x
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发表时间：
1999-02-01
影响因子：
19.6
通讯作者：
Baynes, JW
中科院分区：
文献类型：
--
作者：
Miyata, T;de Strihou, CV;Baynes, JW
晚期糖基化终末产物(AGEs)是在蛋白质非酶糖化和氧化(糖氧化)的Maillard或褐变反应过程中形成的，与糖尿病和尿毒症等多种疾病的发病机制有关。无论是否患有糖尿病，尿毒症患者的血浆蛋白和皮肤胶原中的糖基化终末产物，如戊糖苷和羧甲基赖氨酸，都显著升高。蛋白质的化学修饰增加并不局限于AGEs，因为尿毒症患者的血浆蛋白中也检测到晚期脂氧化终末产物(ALE)水平的增加，如丙二醛。尿毒症血浆蛋白中AGEs和ALE的积累与血糖或甘油三酯的升高无关，也不是由肾小球滤过对化学修饰蛋白的清除减少所决定的。这更可能是由于血浆中AGEs和ALE的小的活性羰基前体浓度增加所致，如乙二醛、甲基乙二醛、3-脱氧葡萄糖苷、脱氢抗坏血酸和丙二醛。因此，尿毒症可以被描述为碳水化合物和脂类氧化增加(氧化应激)或碳水化合物和脂类通过氧化和非氧化化学产生的活性羰基化合物解毒不充分或失活所导致的羰基超负荷或“羰基应激”状态。尿毒症的羰基应激可能导致与慢性肾功能衰竭和透析相关的长期并发症，如透析相关的淀粉样变性和加速的动脉粥样硬化。尿毒症血液和组织蛋白中AGEs和ALE水平的增加表明碳水化合物和脂肪的非酶生物化学存在广泛的紊乱。
Advanced glycation end products (AGEs), formed during Maillard or browning reactions by nonenzymatic glycation and oxidation (glycoxidation) of proteins, have been implicated in the pathogenesis of several diseases, including diabetes and uremia. AGEs, such as pentosidine and carboxymethyllysine, are markedly elevated in both plasma proteins and skin collagen of uremic patients, irrespective of the presence of diabetes. The increased chemical modification of proteins is not limited to AGEs, because increased levels of advanced lipoxidation end products (ALEs), such as malondialdehydelysine, are also detected in plasma proteins in uremia. The accumulation of AGEs and ALEs in uremic plasma proteins is not correlated with increased blood glucose or triglycerides, nor is it determined by a decreased removal of chemically modified proteins by glomerular filtration. It more likely results from increased plasma concentrations of small, reactive carbonyl precursors of AGEs and ALEs, such as glyoxal, methylglyoxal, 3-deoxyglucosone, dehydroascorbate, and malondialdehyde. Thus, uremia may be described as a state of carbonyl overload or "carbonyl stress" resulting from either increased oxidation of carbohydrates and lipids (oxidative stress) or inadequate detoxification or inactivation of reactive carbonyl compounds derived from both carbohydrates and lipids by oxidative and nonoxidative chemistry. Carbonyl stress in uremia may contribute to the long-term complications associated with chronic renal failure and dialysis, such as dialysis-related amyloidosis and accelerated atherosclerosis. The increased levels of AGEs and ALEs in uremic blood and tissue proteins suggest a broad derangement in the nonenzymatic biochemistry of both carbohydrates and lipids.