糖尿病肾病(DKD)是慢性肾病(CKD)背后的罪魁祸首,最终发展为终末期肾病(ESRD),需要昂贵的透析或肾移植。DKD患者的治疗效率有限是我们对其发病机理的有限理解的结果。DKD是各种因素之间复杂相互作用的结果。氧化应激是一个基本因素,可以建立高血糖和糖尿病中经常遇到的血管并发症之间的联系。尤其是DKD。认识到氧化应激在糖尿病血管并发症发展中的重要和不可或缺的作用至关重要。尤其是DKD。高血糖是可引发活性氧(ROS)产生激增的罪魁祸首,最终引发氧化应激。ROS的主要内源性来源包括线粒体ROS的产生,NADPH氧化酶(Nox),非偶联内皮型一氧化氮合酶(eNOS),黄嘌呤氧化酶(XO),细胞色素P450(CYP450),和脂氧合酶.在持续的高葡萄糖水平下,免疫细胞,补充系统,糖基化终产物(AGEs),蛋白激酶C(PKC),多元醇通路,并且己糖胺途径被激活。因此,体内的氧化剂-抗氧化剂平衡被破坏,在各种下游途径中引发一系列反应,包括磷酸肌醇3-激酶/蛋白激酶B(PI3K/Akt),转化生长因子β/p38丝裂原活化蛋白激酶(TGF-β/p38-MAPK),核因子κB(NF-κB),一磷酸腺苷活化蛋白激酶(AMPK),和Janus激酶/信号转导子和转录激活子(JAK/STAT)信号传导。即使实现了严格的血糖控制,这种疾病也可能持续存在,这可以归因于表观遗传修饰。DKD的治疗仍然是一个悬而未决的问题。因此,减少ROS是一个有趣的治疗目标。临床试验表明巴多索隆甲基,一种核因子红系2相关因子2(Nrf2)激活剂,降血糖药物,如钠-葡萄糖协同转运蛋白2抑制剂,胰高血糖素样肽-1受体激动剂可通过降低氧化应激有效减缓DKD的进展。其他抗氧化剂,包括维生素,硫辛酸,Nox抑制剂,表观遗传调节因子,和补体抑制剂,为DKD的治疗提供了一个有希望的治疗选择。在这次审查中,我们对临床前研究和当前临床研究的结果进行了全面评估,这些研究的重点是旨在操纵这些途径的针对性干预措施.我们旨在全面概述该领域的研究现状,并确定未来探索的关键领域。
Diabetic kidney disease (DKD) is the principal culprit behind chronic kidney disease (CKD), ultimately developing end-stage renal disease (ESRD) and necessitating costly dialysis or kidney transplantation. The limited therapeutic efficiency among individuals with DKD is a result of our finite understanding of its pathogenesis. DKD is the result of complex interactions between various factors. Oxidative stress is a fundamental factor that can establish a link between hyperglycemia and the vascular complications frequently encountered in diabetes, particularly DKD. It is crucial to recognize the essential and integral role of oxidative stress in the development of diabetic vascular complications, particularly DKD. Hyperglycemia is the primary culprit that can trigger an upsurge in the production of reactive oxygen species (ROS), ultimately sparking oxidative stress. The main endogenous sources of ROS include mitochondrial ROS production, NADPH oxidases (Nox), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), cytochrome P450 (CYP450), and lipoxygenase. Under persistent high glucose levels, immune cells, the complement system, advanced glycation end products (AGEs), protein kinase C (PKC), polyol pathway, and the hexosamine pathway are activated. Consequently, the oxidant-antioxidant balance within the body is disrupted, which triggers a series of reactions in various downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor beta/p38-mitogen-activated protein kinase (TGF-β/p38-MAPK), nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase (AMPK), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. The disease might persist even if strict glucose control is achieved, which can be attributed to epigenetic modifications. The treatment of DKD remains an unresolved issue. Therefore, reducing ROS is an intriguing therapeutic target. The clinical trials have shown that bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, blood glucose-lowering drugs, such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can effectively slow down the progression of DKD by reducing oxidative stress. Other antioxidants, including vitamins, lipoic acid, Nox inhibitors, epigenetic regulators, and complement inhibitors, present a promising therapeutic option for the treatment of DKD. In this review, we conduct a thorough assessment of both preclinical studies and current findings from clinical studies that focus on targeted interventions aimed at manipulating these pathways. We aim to provide a comprehensive overview of the current state of research in this area and identify key areas for future exploration.