Increased oxidative stress in diabetes regulates activation of asmall molecular weight G-protein, H-Ras, in the retina

[摘要] Purpose: Increased superoxide levels are implicated in thepathogenesis of diabetic retinopathy. We have shown that functionalactivation of a small molecular weight G-protein, H-Ras, is one of thesignaling steps involved in glucose-induced apoptosis of retinalcapillary cells. The goal of this study was to elucidate themechanism(s) by which oxidative stress could result in the activation ofH-Ras in diabetes.Methods: Experiments were performed in isolated retinal endothelialcells that were treated with H2O2, or the cells in whichglucose-induced superoxide accumulation was inhibited either bysuperoxide dismutase mimetic (MnTBAP) or by overexpressing mitochondrialsuperoxide dismutase (MnSOD). The in vitro experiments were complementedwith in vivo experiments using the retina from mice overexpressingMnSOD.Results: H2O2 activated H-Ras and its downstreamsignaling pathway, including Raf-1 and phosphorylation of p38 (p-p38)MAP kinase. Inhibition of superoxide significantly attenuatedglucose-induced activation of H-Ras, Raf-1 and p-p38 MAP kinase.Overexpression of MnSOD in mice prevented diabetes-induced activation ofboth H-Ras and p-p38 MAP kinase.Conclusions: Our results clearly indicate that the activation ofH-Ras and its downstream signaling pathway in the retina and itsvasculature could be under the control of superoxide, and H-Rasactivation in diabetes can be prevented by inhibiting superoxideaccumulation.

[学科分类] 生物化学/生物物理