Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA, 02114, USA.
Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA, 02114, USA; Harvard Medical School, Boston, MA, 02115, USA.
Mol Aspects Med. 2022 Aug;86:101083. doi: 10.1016/j.mam.2022.101083. Epub 2022 Feb 25.
Non-enzymatic post-translational modifications (nPTMs) of proteins have emerged as novel risk factors for the genesis and progression of various diseases. We now have a variety of experimental and established therapeutic strategies to target harmful nPTMs and potentially improve clinical outcomes. Protein carbamylation and glycation are two common and representative nPTMs that have gained considerable attention lately as favorable therapeutic targets with emerging clinical evidence. Protein carbamylation is associated with the occurrence of cardiovascular disease (CVD) and mortality in patients with chronic kidney disease (CKD); and advanced glycation end products (AGEs), a heterogeneous group of molecules produced in a series of glycation reactions, have been linked to various diabetic complications. Therefore, reducing the burden of protein carbamylation and AGEs is an appealing and promising therapeutic approach. This review chapter summarizes potential anti-nPTM therapy options in CKD, CVD, and diabetes along with clinical implications. Using two prime examples-protein carbamylation and AGEs-we discuss the varied preventative and therapeutic options to mitigate these pathologic nPTMs in detail. We provide in-depth case studies on carbamylation in the setting of kidney disease and AGEs in metabolic disorders, with an emphasis on the relevance to reducing adverse clinical outcomes such as CKD progression, cardiovascular events, and mortality. Overall, whether specific efforts to lower carbamylation and AGE burden will yield definitive clinical improvement in humans remains largely to be seen. However, the scientific rationale for such pursuits is demonstrated herein.
蛋白质的非酶促翻译后修饰（nPTMs）已成为各种疾病发生和发展的新的风险因素。我们现在有多种实验和既定的治疗策略来针对有害的 nPTMs，并有可能改善临床结果。蛋白质氨甲酰化和糖基化是两种常见且具有代表性的 nPTMs，最近作为有前途的治疗靶点，具有新的临床证据，受到了相当大的关注。蛋白质氨甲酰化与慢性肾脏病（CKD）患者心血管疾病（CVD）和死亡率的发生有关；而晚期糖基化终产物（AGEs），是一系列糖基化反应产生的一组异质分子，与各种糖尿病并发症有关。因此，减轻蛋白质氨甲酰化和 AGEs 的负担是一种有吸引力和有前途的治疗方法。这篇综述章节总结了 CKD、CVD 和糖尿病中潜在的抗 nPTM 治疗选择及其临床意义。我们使用两个主要的例子——蛋白质氨甲酰化和 AGEs——详细讨论了减轻这些病理性 nPTMs 的各种预防和治疗选择。我们提供了关于肾脏疾病中氨甲酰化和代谢紊乱中 AGEs 的深入案例研究，重点是减少 CKD 进展、心血管事件和死亡率等不良临床结果的相关性。总的来说，是否有具体的努力来降低氨甲酰化和 AGE 负担会对人类产生明确的临床改善，这在很大程度上仍有待观察。然而，这里展示了这种追求的科学原理。
