Compromised DNA repair is responsible for diabetes‐associated fibrosis. (27th April 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO journal. Volume 39:Number 11(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-04-27
• Subjects: diabetes -- DNA double‐strand breaks -- nuclear isoform of the Receptor for Advanced Glycation End products -- pulmonary fibrosis -- reducing carbohydrates; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2019103477
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: Whether persistent DNA damage accounts for the severe organ dysfunctions observed in diabetes is unclear. Here, combined work on cellular and mouse models shows that hyperglycemic conditions and the resultant metabolic alterations cause DNA double‐strand break (DSB)‐dependent inflammation and fibrosis, suggesting a new paradigm for therapeutic interventions. High carbohydrate exposure results in cellular NAD + pool depletion and defective DSB DNA‐repair. High blood glucose is associated with cellular senescence and persistent DNA damage in vivo . Diabetes‐induced, persistent DNA damage is associated with organ fibrosis. Reconstitution of DSB‐DNA repair protects against metabolic stress‐induced fibrosis. Abstract : Persistent DNA damage due to metabolic reprogramming underlies the senescence and fibrotic phenotypes of diabetes patients.