# NADPH oxidase, mitochondrial dysfunction and diabetic retinopathy

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $385,000

## Abstract

Diabetic retinopathy remains a major cause of blindness, and despite cutting edge research in the field, the
molecular mechanism of its pathogenesis remains unclear. Our recent research has shown that during early
stages of this progressing disease, activation of cytosolic NADPH oxidase 2 (Nox2) generates reactive oxygen
species (ROS), and sustained increase in cytosolic ROS damages mitochondrial structure and its DNA,
dysregulating the electron transport chain and initiating a vicious cycle of ROS. Furthermore, we have shown
that dyslipidemia accelerates Nox2-mediated mitochondrial damage and the development of diabetic
retinopathy in a type 2 diabetic animal model. An integral part of the cytosolic core of Nox2 holoenzyme is the
small G-protein, Rac1, and diabetes increases Rac1 activity and gene transcripts in retinal microvasculature.
Rac1 functional activation is mediated by its binding with the guanine exchange factors (GEFs) and guanine
nucleotide dissociation inhibitors (GDIs). Many epigenetic modifications are also favored by diabetic milieu,
and these covalent modifications regulate gene expression without altering the DNA sequence. Thus, the
central hypothesis of the current application is that covalent modifications of Rac1 modulate its functional and
transcriptional activation, and activated Rac1, via Nox2-mediated ROS production, damages the mitochondria,
resulting in accelerated apoptosis and the development of diabetic retinopathy.
Aim 1 will investigate the molecular mechanism(s) by which hyperglycemia promotes activation of Rac1. Our
model predicts that defective prenylation of Rac1 results in its sustained activation and mislocalization, and
dynamic DNA methylation- hydroxymethylation of Rac1 promoter facilitates its transcriptional activation. Aim 2
will delineate the mechanism(s) by which gluco/lipotoxicity accelerates the development of diabetic retinopathy,
and will investigate the effect of dyslipidemia on functional and transcriptional activation of Rac1. Questions
asked under Aim 3 will address the therapeutic potential of regulation of Rac1 activation on inhibition of
diabetic retinopathy, and will test novel small molecule inhibitors of GEF and of ceramide biosynthesis. The
plan will employ fully optimized molecular biological and pharmacological approaches to assess the effect of
diabetes on functional and transcriptional regulation of Rac1 activation in isolated retinal endothelial cells in
culture, and in retinal microvessels from (pre-, type 1 and type 2) diabetic rodent models and from human
donors with established diabetic retinopathy. Our overall goal is to identify novel regulatory mechanisms
involved in the pathogenesis of diabetic retinopathy, specifically at the level of functional and transcriptional
regulation of Rac1. The proposal is based on a testable central hypothesis, and these innovative studies carry
a significant translational impact as they are expected to identify novel therapeutic targets to in...

## Key facts

- **NIH application ID:** 9878860
- **Project number:** 5R01EY022230-07
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** RENU A. KOWLURU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2012-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878860

## Citation

> US National Institutes of Health, RePORTER application 9878860, NADPH oxidase, mitochondrial dysfunction and diabetic retinopathy (5R01EY022230-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9878860. Licensed CC0.

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