Inagi Reiko
Division of Chronic Kidney Disease (CKD) Pathophysiology, The University of Tokyo Graduate School of Medicine, 7-3-1, Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.
Glycoconj J. 2016 Aug;33(4):619-26. doi: 10.1007/s10719-016-9689-8. Epub 2016 Jun 6.
Glycation is an important reaction in the regulation of physiological state. When poorly controlled, however, glycation can also result in the accumulation of glycated proteins (advanced glycation endproducts; AGEs) in the body. This AGE accumulation is termed glycative stress, and is an established pathological factor: to date, glycative stress has been closely associated with not only kidney diseases, but also kidney aging. Accumulating evidence demonstrates that the progression of renal tubular damage and tubular aging are often correlated with activation of the receptor for the AGE (RAGE)-AGE pathway or decreased activity of glyoxalase 1, which is an anti-glycation enzyme to lower glycative stress. Further, glycative stress exacerbates the derangement of protein homeostasis: the posttranslationally modified proteins by glycation often lose or gain their functions. Such deranged protein homeostasis leads to endoplasmic reticulum (ER) stress, a state of ER dysfunction in which the quality control of proteins is defective, as well as to induction of its stress signal, the unfolded protein response (UPR), in the kidney. The lowering of glycative stress via modulation of RAGE-AGE axis or glyoxalase 1 activity is beneficial for tubular homeostasis and the subsequent prevention and treatment of kidney disease, suggesting the possibility of novel therapeutic approaches which target glycative stress. In this review, we focused on the impact of glycative stress in the kidney, especially the role of RAGE and glyoxalase 1. Further we also discuss the crosstalk between glycative stress and ER stress in their effect on protein homeostasis.
糖基化是调节生理状态的重要反应。然而，当控制不佳时，糖基化也会导致体内糖化蛋白（晚期糖基化终产物；AGEs）的积累。这种AGEs的积累被称为糖基化应激，是一种已确定的病理因素：迄今为止，糖基化应激不仅与肾脏疾病密切相关，还与肾脏衰老密切相关。越来越多的证据表明，肾小管损伤和肾小管衰老的进展通常与AGE受体（RAGE）-AGE途径的激活或乙二醛酶1活性的降低有关，乙二醛酶1是一种降低糖基化应激的抗糖基化酶。此外，糖基化应激会加剧蛋白质稳态的紊乱：经糖基化翻译后修饰的蛋白质通常会失去或获得其功能。这种紊乱的蛋白质稳态会导致内质网（ER）应激，即一种内质网功能障碍的状态，其中蛋白质的质量控制存在缺陷，同时也会在肾脏中诱导其应激信号——未折叠蛋白反应（UPR）。通过调节RAGE-AGE轴或乙二醛酶1活性来降低糖基化应激，有利于肾小管稳态以及随后对肾脏疾病的预防和治疗，这表明了针对糖基化应激的新型治疗方法的可能性。在本综述中，我们重点关注糖基化应激在肾脏中的影响，尤其是RAGE和乙二醛酶1的作用。此外，我们还讨论了糖基化应激和内质网应激在影响蛋白质稳态方面的相互作用。
