Defective Autophagy in Diabetic Retinopathy

Area of Science:

• Ophthalmology
• Cell Biology
• Molecular Biology

Background:

• Müller cells (MCs) are a primary source of vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR).
• VEGF is a key therapeutic target for managing DR.
• The role of autophagy in MC response to high glucose (HG) in DR remains to be fully elucidated.

Purpose of the Study:

• To investigate the involvement of autophagy in Müller cell (MC) response under high glucose (HG) conditions.
• To explore the relationship between autophagy, lysosomal function, and VEGF release in MCs exposed to HG.
• To assess the therapeutic potential of modulating autophagy for DR treatment.

Main Methods:

• Rat retinal Müller cells (rMCs) were cultured under normal or high glucose (HG) conditions.
• Pharmacological inhibitors and activators of autophagy, along with siRNA for p62/SQTSM1, were used to manipulate autophagic pathways.
• Autophagic markers, endoplasmic reticulum (ER) stress, apoptosis, lysosomal activity, and VEGF release were analyzed.

Main Results:

• HG induced autophagic marker increase, p62/SQTSM1 accumulation, ER stress, and apoptosis in rMCs.
• Autophagy inhibition exacerbated HG-induced rMC apoptosis, while rapamycin treatment activated autophagy, reduced ER stress, and protected cells.
• Rapamycin improved lysosomal function, restored autophagic degradation, and reduced VEGF release; diabetic rat retinas showed increased Beclin-1 and p62/SQTSM-1 with reduced cathepsin L activity.

Conclusions:

• HG upregulates autophagy in rMCs but leads to lysosomal dysfunction, causing p62/SQTSM1 cargo accumulation, VEGF release, and cell death.
• Lysosomal impairment and autophagic dysfunction are early pathological events in DR.
• Modulating autophagy and lysosomal function presents a promising therapeutic strategy for DR.