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

PURPOSE:Increased superoxide levels are implicated in the pathogenesis of diabetic retinopathy. We have shown that functional activation of a small molecular weight G-protein, H-Ras, is one of the signaling steps involved in glucose-induced apoptosis of retinal capillary cells. The goal of this study was to elucidate the mechanism(s) by which oxidative stress could result in the activation of H-Ras in diabetes. METHODS:Experiments were performed in isolated retinal endothelial cells that were treated with H(2)O(2), or the cells in which glucose-induced superoxide accumulation was inhibited either by superoxide dismutase mimetic (MnTBAP) or by overexpressing mitochondrial superoxide dismutase (MnSOD). The in vitro experiments were complemented with in vivo experiments using the retina from mice overexpressing MnSOD. RESULTS:H(2)O(2) activated H-Ras and its downstream signaling pathway, including Raf-1 and phosphorylation of p38 (p-p38) MAP kinase. Inhibition of superoxide significantly attenuated glucose-induced activation of H-Ras, Raf-1 and p-p38 MAP kinase. Overexpression of MnSOD in mice prevented diabetes-induced activation of both H-Ras and p-p38 MAP kinase. CONCLUSIONS:Our results clearly indicate that the activation of H-Ras and its downstream signaling pathway in the retina and its vasculature could be under the control of superoxide, and H-Ras activation in diabetes can be prevented by inhibiting superoxide accumulation.

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