Sirt1: A Guardian of the Development of Diabetic Retinopathy

摘要

Diabetic retinopathy is a multifactorial disease, and the exact mechanism of its pathogenesis remains obscure. Sirtuin 1 (Sirtl), a multifunctional deacetylase, is implicated in the regulation of many cellular functions and in gene transcription, and retinal Sirtl is inhibited in diabetes. Our aim was to determine the role of Sirtl in the development of diabetic retinopathy and to elucidate the molecular mechanism of its downregulation. Using Sirtl-overexpressing mice that were diabetic for 8 months, structural, functional, and metabolic abnormalities were investigated in vascular and neuronal retina. The role of epigenetjcs in Sirtl transcriptional suppression was investigated in retinal microvessels. Compared with diabetic wild-type mice, retinal vasculature from diabetic Sirtl mice did not present any increase in the number of apoptotic cells or degenerative capillaries or decrease in vascular density. Diabetic Sirtl mice were also protected from mitochondrial damage and had normal electroretinogra-phy responses and ganglion cell layer thickness. Diabetic wild-type mice had hypermethylated Sirtl promoter DNA, which was alleviated in diabetic Sirtl mice, suggesting a role for epigenetics in its transcriptional suppression. Thus strategies targeted to ameliorate Sirtl inhibition have the potential to maintain retinal vascular and neuronal homeostasis, providing opportunities to retard the development of diabetic retinopathy in its early stages.