دورية أكاديمية
Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes
| العنوان: | Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes |
|---|---|
| المؤلفون: | Zheng, Xiaowei, Narayanan, Sampath, Xu, Cheng, Eliasson Angelstig, Sofie, Grünler, Jacob, Zhao, Allan, Di Toro, Alessandro, Bernardi, Luciano, Mazzone, Massimiliano, Carmeliet, Peter, Del Sole, Marianna, Solaini, Giancarlo, Forsberg, Elisabete A, Zhang, Ao, Brismar, Kerstin, Schiffer, Tomas A, Rajamand Ekberg, Neda, Botusan, Ileana Ruxandra, Palm, Fredrik, Catrina, Sergiu-Bogdan |
| المساهمون: | Zheng, Xiaowei, Narayanan, Sampath, Xu, Cheng, Eliasson Angelstig, Sofie, Grünler, Jacob, Zhao, Allan, Di Toro, Alessandro, Bernardi, Luciano, Mazzone, Massimiliano, Carmeliet, Peter, Del Sole, Marianna, Solaini, Giancarlo, Forsberg, Elisabete A, Zhang, Ao, Brismar, Kerstin, Schiffer, Tomas A, Rajamand Ekberg, Neda, Botusan, Ileana Ruxandra, Palm, Fredrik, Catrina, Sergiu-Bogdan |
| سنة النشر: | 2022 |
| المجموعة: | IRIS Università degli Studi di Bologna (CRIS - Current Research Information System) |
| مصطلحات موضوعية: | cell biology, diabete, diabetic complication, human, hypoxia, hypoxia-inducible factor-1, medicine, mitochondria, mouse, reactive oxygen specie, Adult, Animal, Cell Line, Diabetes Complication, Diabetes Mellitu, Female, Hyperglycemia, Hypoxia-Inducible Factor 1, Kidney, Male, Mice, Signal Transduction, Young Adult |
| الوصف: | 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, ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | ELETTRONICO |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/35164902; info:eu-repo/semantics/altIdentifier/wos/WOS:000760317000001; volume:11; firstpage:1; lastpage:22; numberofpages:22; journal:ELIFE; https://hdl.handle.net/11585/909028Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85124680428 |
| DOI: | 10.7554/eLife.70714 |
| الإتاحة: | https://doi.org/10.7554/eLife.70714Test https://hdl.handle.net/11585/909028Test |
| رقم الانضمام: | edsbas.DBED585E |
| قاعدة البيانات: | BASE |
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