Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Centre for Inherited Cardiovascular Diseases, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy.
Elife. 2022 Feb 15;11:e70714. doi: 10.7554/eLife.70714.
Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia.
The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes.
Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes.
We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use.
This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.
线粒体活性氧（ROS）的过度产生是糖尿病并发症发展的核心机制。最近，缺氧被确定在糖尿病中发挥额外的致病作用。在这项研究中，我们假设 ROS 的过度产生是由于高血糖抑制缺氧诱导因子-1（HIF-1），导致对缺氧的反应受损所致。
分析健康受试者和 1 型糖尿病患者在暴露于缺氧后血液中的 ROS 水平。在肾 mIMCD-3 细胞和糖尿病小鼠模型的肾脏中分析 HIF-1、葡萄糖水平、ROS 产生及其功能后果之间的关系。
暴露于缺氧会增加糖尿病患者的循环 ROS，但不会增加非糖尿病患者的循环 ROS。高葡萄糖浓度通过依赖 HIF 脯氨酰羟化酶（PHD）的机制，在缺氧细胞和糖尿病动物的肾脏中抑制 HIF-1。受损的 HIF-1 信号通过增加介导的丙酮酸脱氢酶激酶 1（PDK1）来促进线粒体 ROS 的过度产生。尽管持续高血糖，但恢复 HIF-1 功能可减轻 ROS 过度产生，并在糖尿病中提供对细胞凋亡和肾损伤的保护作用。
我们得出结论，HIF-1 的抑制在糖尿病中线粒体 ROS 的过度产生中起核心作用，是糖尿病并发症的潜在治疗靶点。这些发现是及时的，因为新批准了第一种可以激活 HIF-1 的 PHD 抑制剂用于临床使用。
本工作得到瑞典研究理事会、斯德哥尔摩郡研究理事会、斯德哥尔摩地区研究基金会、Bert von Kantzows 基金会、瑞典医学协会、古斯塔夫五世和王后维多利亚基金会、卡罗林斯卡研究所研究基金会、糖尿病战略研究计划以及 Erling-Persson 家族基金会的资助；得到瑞典研究理事会和瑞典心脏和肺基金会的资助；以及 ERC 巩固者资助。
