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000166280 0247_ $$2doi$$a10.15252/embj.2019103477
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000166280 0247_ $$2ISSN$$a1460-2075
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000166280 037__ $$aDKFZ-2020-02773
000166280 041__ $$aeng
000166280 082__ $$a570
000166280 1001_ $$00000-0003-2827-1024$$aKumar, Varun$$b0
000166280 245__ $$aCompromised DNA repair is responsible for diabetes-associated fibrosis.
000166280 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2020
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000166280 500__ $$a2020 Jun 2;39(11):e103477
000166280 520__ $$aDiabetes-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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000166280 650_7 $$2Other$$aDNA double-strand breaks
000166280 650_7 $$2Other$$adiabetes
000166280 650_7 $$2Other$$anuclear isoform of the Receptor for Advanced Glycation End products
000166280 650_7 $$2Other$$apulmonary fibrosis
000166280 650_7 $$2Other$$areducing carbohydrates
000166280 7001_ $$aAgrawal, Raman$$b1
000166280 7001_ $$aPandey, Aparamita$$b2
000166280 7001_ $$aKopf, Stefan$$b3
000166280 7001_ $$aHoeffgen, Manuel$$b4
000166280 7001_ $$aKaymak, Serap$$b5
000166280 7001_ $$0P:(DE-He78)b11ccde1801d45d32a6a60f7b396d7dc$$aBandapalli, Obul Reddy$$b6$$udkfz
000166280 7001_ $$aGorbunova, Vera$$b7
000166280 7001_ $$aSeluanov, Andrei$$b8
000166280 7001_ $$aMall, Marcus A$$b9
000166280 7001_ $$aHerzig, Stephan$$b10
000166280 7001_ $$00000-0002-6134-7804$$aNawroth, Peter P$$b11
000166280 773__ $$0PERI:(DE-600)1467419-1$$a10.15252/embj.2019103477$$gVol. 39, no. 11$$n11$$pe103477$$tThe EMBO journal$$v39$$x1460-2075$$y2020
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