June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Pentose phosphate pathway and diabetic retinopathy
Author Affiliations & Notes
  • Hu Huang
    University of Missouri, Columbia, Missouri, United States
  • Footnotes
    Commercial Relationships   Hu Huang None
  • Footnotes
    Support  EY027824
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1823. doi:
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      Hu Huang; Pentose phosphate pathway and diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1823.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The pentose phosphate pathway (PPP) is a metabolic pathway parallel to glycolysis, producing NADPH and pentose for cellular redox homeostasis and reductive biosynthesis. Glucose-6-phosphate dehydrogenase (G6PD)-regulated oxidative PPP (oxPPP) is critical for the antioxidant defense of erythrocytes and nucleated cells. The purpose of this study is to investigate the protective role of G6PD-controlled oxPPP in retinal cell injury caused by diabetes and its regulatory mechanism associated with the pathogenesis of diabetic retinopathy (DR).

Methods : The barrier function of retinal EC was assessed by trans-endothelial electrical resistance (TEER) using the electric cell-substrate impedance system (ECIS) system and junction/adhesion proteins’ expression level and cellular localization by RNA sequencing, western blots, and immunofluorescence stain. G6PD gene mutation and knockdown (KD) were performed with CRISPR-Cas9 gene editing and siRNA methods. The in-house made G6PD-floxed mice were bred with Cre recombinase-expressing mice to generate retinal cell-specific G6PD conditional knockout (cKO) mice. Small G6PD activators or agonists were developed to enhance its deficient activity under diabetic conditions.

Results : G6PD’s expression level and enzyme activity are downregulated under diabetic stress conditions in vitro and in vivo. Placental growth factor (PlGF) blockade upregulated PPP metabolic and antioxidant signature gene expression in human retinal endothelial cells (HREC). G6PD inhibition abrogates the beneficial effect of PlGF blockage on HREC’s barrier function, suggesting that G6PD acts as a downstream target of PlGF relevant to DR pathologies. G6PD KO and KD caused increased retinal cell apoptosis by diabetic stress. G6PD inhibition led to increased ROS accumulation by oxidant diamide in HREC and compromised HREC’s response to oxidative stress by H2O2.

Conclusions : Our data suggest that G6PD-regulated oxPPP is regulated by angiogenic factors (e.g., PlGF) and plays a protective role in the retinal cell against diabetes-caused oxidative damage.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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