CONICET | Buscador de Institutos y Recursos Humanos

Müller glial cells (MGs), the majorglial component of the retina, respond to any perceived insult by a reactioncalled reactive gliosis which plays a neuroprotective role but, if persists, itmay lead to neurodegeneration. Understanding the modulation of the glioticresponses is essential for developing efficient therapies. High glucose(HG) concentrations can induce cellular changes that may last evenif glycemic control is achieved. SIRT6, a NAD-dependent sirtuin deacylase,modulates aging, energy metabolism and neurodegeneration. In previous studieswe showed that SIRT6 deficiency causes retinal neurotransmission defects,changes in expression of glycolytic genes and apoptosis. Given the importanceof glucose availability for retinal function, the fact that MGsare a critical source of growth and neural factors, andthe key role of SIRT6 in modulating glycolysis, we aim to analyze SIRT6involvement in MGs function subjected to HG.Primary cultured MGs subjected to HGconcentration (25mM) showed decreased levels of SIRT6 and increased levels ofH3K56 acetylation (p<0,05) than cells treated with low glucose (5mM). Thelevels of the neovascularization promoting factor VEGF increased in MGs underHG (p<0,01) andreverted to control values when SIRT6 was overexpressed. Furthermore, SIRT6silencing resulted in the increment of VEGF levels supporting the idea of SIRT6as a direct modulator of this factor. We also found that HG induced adecrease in the neural factor BDNF levels while this effect was reverted inSIRT6 overexpressing MGs. However, BDNF levels did not showvariations in SIRT6 siRNA expressing cells compared to controls. Moreover,and in accordance to our previous findings in diabetic animals, retinas frommice with conditional deletion of SIRT6 in the CNS exhibited increased levelsof VEGF and lower levels of BDNF than WT (p<0,01). Our results suggest thatHG would induce a neurodegenerative response in MGs that would beepigenetically regulated by SIRT6.