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Defective Autophagy in Diabetic Retinopathy

Jacqueline M Lopes de Faria1, Diego A Duarte1, Chiara Montemurro1

  • 1Renal Pathophysiology Laboratory Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Investigative Ophthalmology & Visual Science
|August 27, 2016
PubMed
Abstract

Insights

High glucose in diabetic retinopathy (DR) upregulates autophagy but impairs lysosomal function, causing Müller cell death and VEGF release. Targeting this dysfunction offers a novel therapeutic strategy for DR.

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.

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