Glycine Suppresses AGE/RAGE Signaling Pathway and Subsequent Oxidative Stress by Restoring Glo1 Function in the Aorta of Diabetic Rats and in HUVECs.

Abstract

Oxidative stress plays a crucial role in the pathogenesis of diabetic vascular complications. It is known that the accumulation of advanced glycation end products (AGEs) and the activation of the receptor of AGEs (RAGE) induce sustained oxidative stress in the vascular tissue. Growing evidence indicates that glycine, the simplest amino acid, exerts antioxidant and antiglycation effects and also improves vascular function. However, the mechanism whereby glycine protects vascular tissue against oxidative stress in models with diabetes has not been investigated. In the present study, we evaluated whether glycine can attenuate oxidative stress by suppressing the AGE/RAGE signaling pathway in the aorta of streptozotocin-induced diabetic rats and in human umbilical vascular endothelial cells (HUVECs). Our results showed that oral glycine administration increased NO content and ameliorated oxidative stress in the serum and aorta of diabetic rats. The AGE/RAGE signaling pathway in the aorta of diabetic rats was significantly attenuated by glycine treatment as manifested by decreases in levels of AGEs, RAGE, Nox4, and NF-κB p65. The suppressive effect of glycine on the formation of AGEs was associated with increased activity and expression of aortic glyoxalase-1 (Glo1), a crucial enzyme that degrades methylglyoxal (MG), the major precursor of AGEs. In MG-treated HUVECs, glycine restored the function of Glo1, suppressed the AGE/RAGE signaling pathway, and inhibited the generation of reactive oxygen species. In addition, the reduction in the formation of AGEs in HUVECs caused by glycine treatment was inhibited by Glo1 inhibition. Taken together, our study provides evidence that glycine might inhibit the AGE/RAGE pathway and subsequent oxidative stress by improving Glo1 function, thus protecting against diabetic macrovascular complications.