TY  - JOUR
AU  - Kumar, Varun
AU  - Agrawal, Raman
AU  - Pandey, Aparamita
AU  - Kopf, Stefan
AU  - Hoeffgen, Manuel
AU  - Kaymak, Serap
AU  - Bandapalli, Obul Reddy
AU  - Gorbunova, Vera
AU  - Seluanov, Andrei
AU  - Mall, Marcus A
AU  - Herzig, Stephan
AU  - Nawroth, Peter P
TI  - Compromised DNA repair is responsible for diabetes-associated fibrosis.
JO  - The EMBO journal
VL  - 39
IS  - 11
SN  - 1460-2075
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DKFZ-2020-02773
SP  - e103477
PY  - 2020
N1  - 2020 Jun 2;39(11):e103477
AB  - 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.
KW  - DNA double-strand breaks (Other)
KW  - diabetes (Other)
KW  - nuclear isoform of the Receptor for Advanced Glycation End products (Other)
KW  - pulmonary fibrosis (Other)
KW  - reducing carbohydrates (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:32338774
C2  - pmc:PMC7265245
DO  - DOI:10.15252/embj.2019103477
UR  - https://inrepo02.dkfz.de/record/166280
ER  -