Abstract
Diabetes mellitus and glaucoma are the two major causes of selective retinal ganglion cell (RGC) death. To determine the relationship between autophagy and RGC death, we compared autophagy and the related molecular pathways in diabetic and glaucomatous retinas and examined their effect on RGC survival. Biochemical analysis of microtubule-associated protein light chain 3 (LC3)-II and beclin-1 were observed. To determine the pathways involved in autophagy induction, adenosine monophosphate-activated protein kinase (AMPK) and the mechanistic target of rapamycin (mTOR) were also explored. Beclin-1 and the LC3B-II to LC3B-I ratio significantly elevated at 4 and 8 weeks after glaucoma induction; however, only a slight increase was apparent in the diabetic retina. Significant upregulation of phosphorylated AMPK and downregulation of phosphorylated mTOR was evident in the diabetic retina. After autophagy was inhibited with 3-methyladenine (3-MA), apoptosis of RGCs was significantly increased in the diabetic retinas. However, 3-MA inhibition of autophagy decreased the apoptosis of RGCs in glaucomatous retinas. Therefore, our results suggest that RGC death is differentially regulated by autophagy and that the pathways involved differ depending on the triggering injury.
Highlights
Retinal ganglion cell (RGC) death occurs in a variety of ocular diseases
Our results suggest that autophagy is activated in retinal ganglion cell (RGC) in both diabetic and glaucomatous retinas; its role in RGC survival appears to differ in two conditions
Chronic elevation of intraocular pressure (IOP) in glaucoma triggers a gradual increase in beclin-1 and LC3B-II in the absence of AMPK involvement
Summary
Retinal ganglion cell (RGC) death occurs in a variety of ocular diseases. Diabetes mellitus and glaucoma are the two major causes of selective RGC death in the retina. Studies investigating the role of autophagy have produced conflicting results to RGC death in the diabetic and glaucomatous retina[17]. Whether autophagy promotes survival by restoring cell function or triggers autophagic cell death mechanism may be related to the initial injury. In a study with an animal model of glaucoma with chronic and mild elevated IOP, autophagy promoted cell death[18]. In this situation, the injury may have triggered growth factor deprivation in the RGCs. When growth factor deprivation occurs, the phosphoinositide 3-kinase (PI3K) pathway is downregulated, and B-cell lymphoma 2 (Bcl-2)/B-cell lymphoma-extra large (Bcl-xL) are decreased, which releases www.nature.com/scientificreports/. To determine the role of autophagy in RGCs, we compared autophagy in diabetic and glaucomatous retinas, examined related molecular pathways, and determined the effects on RGC survival
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