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增进eNOS二聚体活性进而改变NO与ONOO−比例是治疗糖尿病肾病的新方向

阚启明¹, 胡耀豪^1,*, 何仲贵²

¹沈阳药科大学生命科学与生物制药学院，沈阳 110016；²沈阳药科大学无涯创新学院，沈阳 110016

摘要

糖尿病肾病是糖尿病微血管并发症之一，其发病与代谢失调所致内皮功能障碍相关。血管内皮合成的NO有重要的生理活性，参与肾小球滤过和内皮保护功能。糖尿病肾病会出现NO代谢通路失调，很有可能是糖尿病肾病发展的关键原因。高血糖和脂质紊乱可导致氧化应激、慢性炎症和胰岛素抵抗状态，从而影响由内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS)及其相关蛋白和分子构成的调控体系，其中，对糖尿病肾病的发展最为关键的是NO和超氧阴离子(O2. −)结合生成的过氧亚硝基阴离子(ONOO−)。ONOO−有极高的氧化能力，会促使eNOS脱偶联，而脱偶联的eNOS不合成NO而合成O2. −，这是造成NO代谢失调的主要原因。了解NO的调控机制及不同病理状态对其产生的影响，将有利于深入了解糖尿病肾病的病理生理，对发现潜在药物靶点或作用机制具有重要意义。我们认为，增加eNOS二聚体的稳定性与活性，促进NO生成，提高NO/ONOO−的比例，可作为指导糖尿病肾病药物研发的理论基础，本综述将以一些临床药物的作用加以说明。

关键词： 糖尿病肾病; 内皮型一氧化氮合酶; 一氧化氮; 过氧亚硝酸; 氧化应激

Normalization of the ratio of nitric oxide and peroxynitrite by promoting eNOS dimer activity is a new direction for diabetic nephropathy treatment

KAN Qi-Ming¹, HU Yao-Hao^1,*, HE Zhong-Gui²

¹School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China；²Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China

Abstract

Diabetic nephropathy is a microvascular complication of diabetes. Its etiology involves metabolic disorder-induced endothelial dysfunction. Endothelium-derived nitric oxide (NO) plays an important role in a number of physiological processes, including glomerular filtration and endothelial protection. NO dysregulation is an important pathogenic basis of diabetic nephropathy. Hyperglycemia and dyslipidemia can lead to oxidative stress, chronic inflammation and insulin resistance, thus affecting NO homeostasis regulated by endothelial nitric oxide synthase (eNOS) and a conglomerate of related proteins and factors. The reaction of NO and superoxide (O2.−) to form peroxynitrite (ONOO−) is the most important pathological NO pathway in diabetic nephropathy. ONOO− is a hyper-reactive oxidant and nitrating agent in vivo which can cause the uncoupling of eNOS. The uncoupled eNOS does not produce NO but produces superoxide. Thus, eNOS uncoupling is a critical contributor of NO dysregulation. Understanding the regulatory mechanism of NO and the effects of various pathological conditions on it could reveal the pathophysiology of diabetic nephropathy, potential drug targets and mechanisms of action. We believe that increasing the stability and activity of eNOS dimers, promoting NO synthesis and increasing NO/ONOO− ratio could guide the development of drugs to treat diabetic nephropathy. We will illustrate these actions with some clinically used drugs as examples in the present review.

Key words: diabetic nephropathy; endothelial nitric oxide synthase; nitric oxide; peroxynitrous acid; oxidative stress

收稿日期：　　录用日期：

通讯作者：胡耀豪　　E-mail: yiuhowoo@syphu.edu.cn

DOI: 10.13294/j.aps.2022.0009

引用本文：

阚启明, 胡耀豪, 何仲贵. 增进eNOS二聚体活性进而改变NO与ONOO−比例是治疗糖尿病肾病的新方向[J]. 生理学报 2022; 74 (1): 93-109.

KAN Qi-Ming, HU Yao-Hao, HE Zhong-Gui. Normalization of the ratio of nitric oxide and peroxynitrite by promoting eNOS dimer activity is a new direction for diabetic nephropathy treatment. Acta Physiol Sin 2022; 74 (1): 93-109 (in Chinese with English abstract).