Centre for Inherited Cardiovascular Diseases, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy
Luciano Bernardi
Folkälsan Research Center, Folkälsan Institute of Genetics, University of Helsinki, Helsinki, Finland
Massimiliano Mazzone
Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB); Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Katholieke Universiteit (KU) Leuven; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium
Marianna Del Sole
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Giancarlo Solaini
Dipartimento di Biochimica, Università di Bologna, Bologna, Italy
Elisabete A Forsberg
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Ao Zhang
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Kerstin Brismar
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Tomas A Schiffer
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Center for Diabetes, Academic Specialist Centrum, Stockholm, Sweden
Ileana Ruxandra Botusan
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Center for Diabetes, Academic Specialist Centrum, Stockholm, Sweden
Fredrik Palm
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology and Diabetes, Karolinska University Hospital, Stockholm, Sweden; Center for Diabetes, Academic Specialist Centrum, 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.
