CONICET | Buscador de Institutos y Recursos Humanos

Diabeticretinopathy (DR) is the leading cause of blindness worldwide. Recent researchhas demonstrated that DR is not only a microvascular disease but may be aresult of neurodegenerative processes. Currentinvestigation points to the role of histone acetyl transferases anddeacetylases as regulators of key genes linked to diabetes. SIRT6, a NAD-dependent deacylase, modulates aging, cancer, energymetabolism, neurodegeneration and DNA repair. In previous studies we showedthat SIRT6 deficiency causes major retinal transmission defects related tochanges in expression of glycolytic genes and glutamate receptors, as well aselevated levels of apoptosis in inner retina cells. Given the importance ofglucose availability for retina function and the critical role for SIRT6 inmodulating glycolysis, the main goal of this work was to analyze SIRT6involvement in the molecular machinery that regulates the development ofexperimental DR. Using the non-obese diabetic (NOD) mouse strain that spontaneously develops type 1Diabetes, we determinedby Western blot and RT-PCR that high glucose concentrations (>200 mg/dl) induced increased VEGF (p<0,01)and decreased BDNF retinal levels (p<0,01). Moreover, FOXO1 levels, known for modulating gluconeogenesis, were increased inretinas from NOD diabetic vs. control mice. Additionally, significantly lower SIRT6 levels (p<0,05)associated with increased H3K56 acetylation levels (p<0,01) were shown inretinas from NOD diabetic mice compared to controls. Interestingly, retinas fromSIRT6-KO mice showed a resemblance to diabetic retinas exhibiting lower levelsof BDNF and increased levels of VEGF and FOXO1. Noteworthy, immunofluorescencestudies showed that GFAP levels were increased in NOD diabetic but not in SIRT6-KOretinas. Our results suggest that neurodegenerative events regulatedepigenetically may occur early during diabetes development precedingproliferative, vascular and histological changes observed later in a diabetic retina.