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Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in
Xiaowei Zheng1, Sampath Narayanan1, Cheng Xu1
1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Funding:
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.
Insights
Hyperglycemia impairs hypoxia-inducible factor-1 (HIF-1) signaling, leading to excessive mitochondrial reactive oxygen species (ROS) production and diabetic complications. Restoring HIF-1 function mitigates ROS overproduction and protects against kidney injury in diabetes.
Area of Science:
- Endocrinology
- Cellular Biology
- Pathophysiology
Background:
- Excessive mitochondrial reactive oxygen species (ROS) production is a key factor in diabetes complications.
- Hypoxia has emerged as an additional pathogenic factor in diabetes.
- This study investigates the link between hyperglycemia, impaired hypoxia response, and ROS overproduction via hypoxia-inducible factor-1 (HIF-1).
Purpose of the Study:
- To test the hypothesis that hyperglycemia inhibits hypoxia-inducible factor-1 (HIF-1) signaling, leading to ROS overproduction and diabetic complications.
- To elucidate the role of HIF-1 in mediating the cellular response to hypoxia in the context of diabetes.
Main Methods:
- Analyzed ROS levels in healthy subjects and type 1 diabetes patients after hypoxia exposure.
- Investigated the relationship between HIF-1, glucose levels, ROS production, and functional outcomes in renal cells and diabetic mouse models.
Main Results:
- Hypoxia increased ROS in diabetic subjects but not in healthy individuals.
- Hyperglycemia repressed HIF-1 through a HIF prolyl-hydroxylase (PHD)-dependent mechanism, increasing mitochondrial ROS via Pyruvate dehydrogenase kinase 1 (PDK1).
- Restoring HIF-1 function reduced ROS, protected against apoptosis, and mitigated renal injury in diabetic models, even with persistent hyperglycemia.
Conclusions:
- HIF-1 repression is central to mitochondrial ROS overproduction in diabetes and a potential therapeutic target.
- These findings are significant given the recent approval of a PHD inhibitor for clinical use, which can activate HIF-1.
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