# Glycemic Control and Progession of Diabetic Retinopathy

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

## Abstract

ABSTRACT
Diabetic retinopathy remains the leading cause of blindness in working-age adults. Landmark clinical studies
have documented that even after achieving and maintaining good glycemic control for many years, damage
instilled by the prior poor glycemic control becomes difficult to undo, and the results have suggested that the
prior hyperglycemia leaves a legacy. This `metabolic
memory' phenomenon is also duplicated in vitro and in
vivo experimental models of diabetic retinopathy. Termination of hyperglycemia in rats does not reverse
mitochondrial dysfunction and DNA (mtDNA) damage,
DNA repair enzyme MutL homolog 1 (Mlh1) remains
subnormal, and impaired mtDNA
transcription continues to compromise the
electron transport chain (ETC).
Stability of both genomic and structure/physiology are important for mitochondrial homeostasis; mitochondrial
fusion enzyme mitofusin 2 (Mfn2) also remains subnormal even after cessation of hyperglycemia. Recent
studies have documented that genomic functions are also modulated by epigenetic modifications, the
modifications that regulate gene expression without changing the DNA sequence. Our recent research has
shown that diabetes activates DNA methylation machinery in the retina and its capillary cells, and this
activation is not terminated by reversal of hyperglycemia. Thus, the central hypothesis is that due to sustained
epigenetic modifications, mitochondrial DNA and structure/function remain damaged. Dysfunctional
mitochondria continues to fuel into the vicious cycle of free radicals, and cessation of hyperglycemia fails to
arrest the progression of incipient diabetic retinopathy.
Aim 1 will investigate the role of epigenetic modification in mitochondrial genomic stability. Our model predicts
that due to sustained Mlh1 promoter DNA hypermethylation, mitochondrial genomic stability remains
compromised, and impaired mtDNA transcription continues to damage ETC system, fueling into mitochondrial
damage. Aim 2 will determine how epigenetic modifications regulate mitochondrial structural/physiological
homeostasis, and will investigate the role of epigenetic modifications of Mfn2 promoter in continued
mitochondrial damage. Aim 3 will determine the effect of protection of mitochondrial homeostasis in the
resistance of diabetic retinopathy to halt by directly inhibiting epigenetic modifications during normal glycemia,
which has followed hyperglycemia. The plan will employ in vitro (retinal endothelial cells) and in vivo (retinal
microvessels from rodents maintained in varied glycemic control) models of metabolic memory, and will utilize
fully optimized molecular biological and pharmacological approaches. Our overall goal is to understand the
molecular mechanism responsible for continued mitochondrial damage in the progression of diabetic
retinopathy. The proposal is based on a testable central hypothesis, and these innovative studies carry a
significant translational impact as they are expected to define the role of epi...

## Key facts

- **NIH application ID:** 9899997
- **Project number:** 5R01EY017313-09
- **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:** 2007-03-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899997

## Citation

> US National Institutes of Health, RePORTER application 9899997, Glycemic Control and Progession of Diabetic Retinopathy (5R01EY017313-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899997. Licensed CC0.

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