Leptin mediates hyperglycemia-induced angiogenic effects in retinal endothelial cells

Abstract

Hyperglycemia (HG)-activated cytokines and inflammatory factors have been implicated in ocular neovascularization and diabetic retinopathy (DR). However, the effects of HG on the expression and function of leptin in retinal cells have never been investigated. We found that in RF/6A retinal endothelial cells, chronic high glucose (30 mM/L) exposure significantly increased leptin mRNA expression and upregulated leptin protein and leptin receptor levels. Furthermore, HG potentiated RF/6A cell migration, chemokinesis, and angiogenic differentiation. These effects coincided with the activation of several intracellular pathways implicated in angiogenic and metabolic response, i.e., STAT3, ERK1/2, Akt, and AMPK, increased levels of glucose response protein and COX2 as well as modulation of the expression of PAI-2 and HIF-1α. All pro-angiogenic processes promoted by HG and several of HG-activated intracellular pathways were partially or totally blocked in the presence of the leptin receptor antagonist peptide. The results demonstrate for the first time that the leptin/leptin receptor axis is implicated in HG-induced biological effects in retinal endothelial cells. Thus, targeting leptin pathways might represent a novel avenue in the treatment of ocular neovascularization