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Kumar, V.* ; Agrawal, R.* ; Pandey, A.* ; Kopf, S.* ; Hoeffgen, M.* ; Kaymak, S.* ; Bandapalli, O.R.* ; Gorbunova, V.* ; Seluanov, A.* ; Mall, M.A.* ; Herzig, S. ; Nawroth, P.P.

Compromised DNA repair is responsible for diabetes-associated fibrosis.

EMBO J. 39:e103477 (2020)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Diabetes ; Dna Double-strand Breaks ; Nuclear Isoform Of The Receptor For Advanced Glycation End Products ; Pulmonary Fibrosis ; Reducing Carbohydrates; Glycation End-products; Redox-optimized Ros; Cellular Senescence; Pulmonary-fibrosis; Beta-galactosidase; Telomerase Mutations; Premature Senescence; Monogenic Diseases; Oxidative Stress; Oxygen-tension
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 39, Heft: 11, Seiten: , Artikelnummer: e103477 Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)