Biochemical Functions and Clinical Characterizations of the Sirtuins in Diabetes-Induced Retinal Pathologies

Abstract

Diabetic retinopathy (DR) is undoubtedly one of the most prominent causes of blindness worldwide. This pathology is the most frequent microvascular complication arising from diabetes, and its incidence is increasing at a constant pace. To date, the insurgence of DR is thought to be the consequence of the intricate complex of relations connecting inflammation, the generation of free oxygen species, and the consequent oxidative stress determined by protracted hyperglycemia. The sirtuin (SIRT) family comprises 7 histone and non-histone protein deacetylases and mono (ADP-ribosyl) transferases regulating different processes, including metabolism, senescence, DNA maintenance, and cell cycle regulation. These enzymes are involved in the development of various diseases such as neurodegeneration, cardiovascular pathologies, metabolic disorders, and cancer. SIRT1, 3, 5, and 6 are key enzymes in DR since they modulate glucose metabolism, insulin sensitivity, and inflammation. Currently, indirect and direct activators of SIRTs (such as antagomir, glycyrrhizin, and resveratrol) are being developed to modulate the inflammation response arising during DR. In this review, we aim to illustrate the most important inflammatory and metabolic pathways connecting SIRT activity to DR, and to describe the most relevant SIRT activators that might be proposed as new therapeutics to treat DR.

Keywords: anti-VEGF; antioxidants; diabetes mellitus; diabetic retinopathy; free radicals; neuroinflammation; oxidative stress; sirtuins.

Figure 1

(A) Structure of the naturally occurring compound glycyrrhizin, possessing an indirect effect on SIRT1 activity. (B) Structures and enzymatic activities of direct SIRT1 activators resveratrol, SRT1460, SRT1720, and SRT2183.

Figure 2

This schema summarizes that Sirt1 expression is reduced in the vascular hyperglycemia.