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Sökning: WFRF:(Ekberg Peter) > (2020-2024) > Repression of hypox...

  • Zheng, XiaoweiKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)

Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes

  • Artikel/kapitelEngelska2022

Förlag, utgivningsår, omfång ...

  • eLife Sciences Publications Ltd,2022
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-469764
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-469764URI
  • https://doi.org/10.7554/eLife.70714DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

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Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Narayanan, SampathKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)
  • Xu, ChengKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)
  • Eliasson Angelstig, SofieKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)
  • Grunler, JacobKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)
  • Zhao, AllanKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)
  • Di Toro, AlessandroIRCCS Fdn Univ Hosp Policlin San Matteo, Ctr Inherited Cardiovasc Dis, Pavia, Italy. (författare)
  • Bernardi, LucianoUniv Helsinki, Folkalsan Inst Genet, Folkalsan Res Ctr, Helsinki, Finland. (författare)
  • Mazzone, MassimilianoKatholieke Univ KU Leuven, Vlaams Inst Biotechnol VIB, Ctr Canc Biol,Dept Oncol, Lab Tumor Inflammat & Angiogenesis,Ctr Canc Biol, Leuven, Belgium. (författare)
  • Carmeliet, PeterKatholieke Univ KU Leuven, Vlaams Inst Biotechnol VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab,Dept Oncol, Leuven, Belgium. (författare)
  • Del Sole, MariannaKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)
  • Solaini, GiancarloUniv Bologna, Dipartimento Biochim, Bologna, Italy. (författare)
  • Forsberg, Elisabete A.Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)
  • Zhang, AoKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;GuangDong Second Tradit Chinese Med Hosp, Dept Nephrol, Guangzhou, Peoples R China. (författare)
  • Brismar, KerstinKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (författare)
  • Schiffer, Tomas A.Uppsala universitet,Institutionen för medicinsk cellbiologi (författare)
  • Rajamand Ekberg, NedaKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol & Diabet, Stockholm, Sweden.;Acad Specialist Centrum, Ctr Diabet, Stockholm, Sweden. (författare)
  • Botusan, Ileana RuxandraKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol & Diabet, Stockholm, Sweden.;Acad Specialist Centrum, Ctr Diabet, Stockholm, Sweden. (författare)
  • Palm, Fredrik,1973-Uppsala universitet,Integrativ Fysiologi(Swepub:uu)fredpalm (författare)
  • Catrina, Sergiu-BogdanKarolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol & Diabet, Stockholm, Sweden.;Acad Specialist Centrum, Ctr Diabet, Stockholm, Sweden. (författare)
  • Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.IRCCS Fdn Univ Hosp Policlin San Matteo, Ctr Inherited Cardiovasc Dis, Pavia, Italy. (creator_code:org_t)

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  • Ingår i:eLIFE: eLife Sciences Publications Ltd112050-084X

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