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Compromised DNA repair is responsible for diabetes-associated fibrosis

Diabetes-associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern. Intriguingly, the mechanism underlying this association remained unknown. Moreover, insulin alone can neither reverse organ fibrosis nor the associated secretory phenotype, favoring the exciting...

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Hauptverfasser: Kumar, Varun (Verfasst von) , Agrawal, Raman (Verfasst von) , Pandey, Aparamita (Verfasst von) , Kopf, Stefan (Verfasst von) , Höffgen, Manuel (Verfasst von) , Kaymak, Serap (Verfasst von) , Bandapalli, Obul Reddy (Verfasst von) , Gorbunova, Vera (Verfasst von) , Seluanov, Andrei (Verfasst von) , Mall, Marcus A. (Verfasst von) , Herzig, Stephan (Verfasst von) , Nawroth, Peter Paul (Verfasst von)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 27 April 2020
In: The EMBO journal
Year: 2020, Jahrgang: 39, Heft: 11
ISSN:1460-2075
DOI:10.15252/embj.2019103477
Online-Zugang:Resolving-System, kostenfrei, Volltext: https://doi.org/10.15252/embj.2019103477
Verlag, kostenfrei, Volltext: https://www.embopress.org/doi/full/10.15252/embj.2019103477
Volltext
Verfasserangaben:Varun Kumar, Raman Agrawal, Aparamita Pandey, Stefan Kopf, Manuel Hoeffgen, Serap Kaymak, Obul Reddy Bandapalli, Vera Gorbunova, Andrei Seluanov, Marcus A Mall, Stephan Herzig & Peter P Nawroth
Beschreibung
Zusammenfassung:Diabetes-associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern. Intriguingly, the mechanism underlying this association remained unknown. Moreover, insulin alone can neither reverse organ fibrosis nor the associated secretory phenotype, favoring the exciting notion that thus far unknown mechanisms must be operative. Here, we show that experimental type 1 and type 2 diabetes impairs DNA repair, leading to senescence, inflammatory phenotypes, and ultimately fibrosis. Carbohydrates were found to trigger this cascade by decreasing the NAD+/NADH ratio and NHEJ-repair in vitro and in diabetes mouse models. Restoring DNA repair by nuclear over-expression of phosphomimetic RAGE reduces DNA damage, inflammation, and fibrosis, thereby restoring organ function. Our study provides a novel conceptual framework for understanding diabetic fibrosis on the basis of persistent DNA damage signaling and points to unprecedented approaches to restore DNA repair capacity for resolution of fibrosis in patients with diabetes.
Beschreibung:Gesehen am 19.06.2020
Beschreibung:Online Resource
ISSN:1460-2075
DOI:10.15252/embj.2019103477

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