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.
Highlights
Diabetes-associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern
To understand the role of high O2 tension and mitochondrial energetics in DNA damage, mitochondrial DNA was quantified in lung tissue obtained directly after birth and the subsequent postnatal days
Exposure of the lung to the environmental O2 concentration resulted in an increase in mitochondrial DNA (Fig 1A and B), ROS formation (Fig 1C and Appendix Fig S1A), and a slight elevation in inflammation marker IL-6 (Appendix Fig S1B)
Summary
Diabetes-associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern. The mechanism underlying this association remained unknown. Insulin alone can neither reverse organ fibrosis nor the associated secretory phenotype, favoring the exciting notion that far unknown mechanisms must be operative. We show that experimental type 1 and type 2 diabetes impairs DNA repair, leading to senescence, inflammatory phenotypes, and fibrosis. Restoring DNA repair by nuclear overexpression 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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