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Compromised DNA repair is responsible for diabetes‐associated fibrosis
Author(s) -
Kumar Varun,
Agrawal Raman,
Pandey Aparamita,
Kopf Stefan,
Hoeffgen Manuel,
Kaymak Serap,
Bandapalli Obul Reddy,
Gorbunova Vera,
Seluanov Andrei,
Mall Marcus A,
Herzig Stephan,
Nawroth Peter P
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103477
Subject(s) - fibrosis , biology , dna repair , dna damage , senescence , inflammation , diabetes mellitus , microbiology and biotechnology , phenotype , glycation , dna , immunology , cancer research , genetics , endocrinology , medicine , gene
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.