Neural degeneration mechanisms in diabetic retinopathy: The role of apoptosis and autophagy

Purpose That neuronal injury plays a major role in diabetic retinopathy (DR) is gaining increasing recognition. In particular, we have recently shown, using an ex vivo model of early DR, that neuroprotection may also reduce the expression of proangiogenic factors. Given the importance of neuronal health in DR, we chose to better analyze the mechanisms of cell death involved in this disease. Our hypothesis was that the balance between neuronal death and survival may depend on a similar equilibrium between apoptosis and autophagy: in this context, a neuroprotective treatment would act by influencing this equilibrium. Methods Ex vivo mouse retinal explants were treated with high glucose (HG, 75 mM) for 10 days and the somatostatin analog octreotide (OCT, 1µM) was used as a neuroprotectant. Chloroquine (CQ, 10µM) was used as an autophagy inhibitor. Apoptotic and autophagic markers were evaluated using  Western blot and immunohistochemistry. Results Consistent with our previous observations, HG-treated retinal explants displayed a significant increase of apoptosis. Concurrently, HG treatment caused a significant decrease of the autophagic flux, which was likely to be due to increased activity of the autophagy regulator mTOR. Treatment with OCT rescued HG-treated retinal explants from apoptosis and determined an increase of autophagic activity with concomitant mTOR inhibition. Blocking the autophagic flux with CQ completely abolished the anti-apoptotic effect of OCT. Conclusions Apoptosis and autophagy seem to play opposite roles and a delicate balance between apoptotic and autophagic fluxes is responsible for the death or survival of retinal neurons in stressing conditions like HG. Consistently, the data obtained with CQ suggest that the anti-apoptotic effect of OCT in HG-treated retinas is mediated by an increase of the autophagic flux.