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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

Received: 　　Accepted:

Corresponding author: 胡耀豪　　E-mail: yiuhowoo@syphu.edu.cn

DOI: 10.13294/j.aps.2022.0009

Citing This Article：

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).