PMID- 35164902 OWN - NLM STAT- MEDLINE DCOM- 20220302 LR - 20220302 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 11 DP - 2022 Feb 15 TI - Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes. LID - 10.7554/eLife.70714 [doi] LID - e70714 AB - 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. CI - (c) 2022, Zheng et al. FAU - Zheng, Xiaowei AU - Zheng X AUID- ORCID: 0000-0002-2648-1119 AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Narayanan, Sampath AU - Narayanan S AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Xu, Cheng AU - Xu C AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Eliasson Angelstig, Sofie AU - Eliasson Angelstig S AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Grunler, Jacob AU - Grunler J AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Zhao, Allan AU - Zhao A AUID- ORCID: 0000-0002-2492-0923 AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Di Toro, Alessandro AU - Di Toro A AUID- ORCID: 0000-0001-7625-1103 AD - Centre for Inherited Cardiovascular Diseases, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy. FAU - Bernardi, Luciano AU - Bernardi L AD - Folkalsan Research Center, Folkalsan Institute of Genetics, University of Helsinki, Helsinki, Finland. FAU - Mazzone, Massimiliano AU - Mazzone M AD - 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. FAU - Carmeliet, Peter AU - Carmeliet P AUID- ORCID: 0000-0001-7961-1821 AD - 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. FAU - Del Sole, Marianna AU - Del Sole M AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Solaini, Giancarlo AU - Solaini G AD - Dipartimento di Biochimica, Universita di Bologna, Bologna, Italy. FAU - Forsberg, Elisabete A AU - Forsberg EA AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Zhang, Ao AU - Zhang A AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Brismar, Kerstin AU - Brismar K AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Schiffer, Tomas A AU - Schiffer TA AD - Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. FAU - Rajamand Ekberg, Neda AU - Rajamand Ekberg N AUID- ORCID: 0000-0001-5597-2593 AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. AD - Department of Endocrinology and Diabetes, Karolinska University Hospital, Stockholm, Sweden. AD - Center for Diabetes, Academic Specialist Centrum, Stockholm, Sweden. FAU - Botusan, Ileana Ruxandra AU - Botusan IR AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. AD - Department of Endocrinology and Diabetes, Karolinska University Hospital, Stockholm, Sweden. AD - Center for Diabetes, Academic Specialist Centrum, Stockholm, Sweden. FAU - Palm, Fredrik AU - Palm F AD - Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. FAU - Catrina, Sergiu-Bogdan AU - Catrina SB AUID- ORCID: 0000-0002-6914-3902 AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. AD - Department of Endocrinology and Diabetes, Karolinska University Hospital, Stockholm, Sweden. AD - Center for Diabetes, Academic Specialist Centrum, Stockholm, Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220215 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (Hypoxia-Inducible Factor 1) RN - 0 (Reactive Oxygen Species) SB - IM MH - Adult MH - Animals MH - Cell Line MH - Diabetes Complications MH - Diabetes Mellitus/blood/*genetics MH - Female MH - Humans MH - Hyperglycemia/genetics MH - *Hypoxia MH - Hypoxia-Inducible Factor 1/*antagonists & inhibitors/*genetics MH - Kidney/pathology MH - Male MH - Mice MH - Mitochondria/*metabolism MH - Reactive Oxygen Species/*blood/*metabolism MH - Signal Transduction MH - Young Adult PMC - PMC8846593 OTO - NOTNLM OT - cell biology OT - diabetes OT - diabetic complications OT - human OT - hypoxia OT - hypoxia-inducible factor-1 OT - medicine OT - mitochondria OT - mouse OT - reactive oxygen species COIS- XZ, SN, CX, SE, JG, AZ, AD, LB, MM, PC, MD, GS, EF, AZ, KB, TS, NR, IB, FP, SC No competing interests declared EDAT- 2022/02/16 06:00 MHDA- 2022/03/03 06:00 PMCR- 2022/02/15 CRDT- 2022/02/15 05:32 PHST- 2021/05/26 00:00 [received] PHST- 2022/01/27 00:00 [accepted] PHST- 2022/02/15 05:32 [entrez] PHST- 2022/02/16 06:00 [pubmed] PHST- 2022/03/03 06:00 [medline] PHST- 2022/02/15 00:00 [pmc-release] AID - 70714 [pii] AID - 10.7554/eLife.70714 [doi] PST - epublish SO - Elife. 2022 Feb 15;11:e70714. doi: 10.7554/eLife.70714.