# A new pathogenic mechanism for diabetic retinopathy

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $351,625

## Abstract

PROJECT SUMMARY/ABSTRACT
Diabetes-induced oxidative stress and chronic inflammation in the retina play a key pathogenic role in diabetic
retinopathy (DR). Mitochondrial dysfunction and impairment have been identified as the major cause of
oxidative stress and inflammation in DR. Peroxisome Proliferator-Activated Receptor α (PPARα) is a hormone-
activated receptor and transcription factor. It is known to regulate lipid metabolism, and thus, PPARα agonists
are used clinically to treat hyperlipidemia. Recently, two independent, prospective clinical studies reported a
surprising finding that oral administration of fenofibrate, a PPARα agonist, has robust therapeutic effects on DR
in type 2 diabetic patients. In the prior grant period, we have successfully demonstrated that the therapeutic
effect of fenofibrate on DR is through a PPARα-dependent mechanism. We have shown that PPARα is down-
regulated in the retinas of diabetic humans and diabetic animal models, and PPARα has protective effects
against DR. We have shown that PPARα knockout (KO) exacerbated, while activation of PPARα by fenofibrate
alleviated retinal oxidative stress and retinal inflammation in DR models. This proposal will extend these
studies and elucidate the mechanism responsible for the protective effects of PPARα. Our preliminary studies
showed that fenofibrate treatment decreased diabetes-induced acellular capillary formation and pericyte loss in
the retina. Further, Seahorse analysis showed that PPARα KO resulted in mitochondrial dysfunction in the
retina and primary pericytes. Further, PPARα-/- retina showed decreased mitochondrial DNA (mtDNA) copy
numbers, suggesting impaired mitochondrial biogenesis and/or DNA repair. This project will address a novel
hypothesis that diabetes-induced down-regulation of PPARα expression is responsible for, at least in part, for
diabetes-induced mitochondrial dysfunction, which leads to retinal oxidative stress and inflammation in DR. We
will determine if PPARα KO exacerbates, while PPARα over-expression alleviates, mitochondrial dysfunction
(basal OCR, maximal OCR and ATP production) and mtDNA damage as well as retinal oxidative stress,
leukostasis, vascular leakage, acellular capillary formation and pericyte dropout in the retina of diabetic mice.
We will also determine the impacts of PPARα deficiency in pericytes on diabetes-induced mitochondrial
damage, oxidative stress and pericyte apoptosis using pericyte-specific conditional PPARα KO mice and
primary PPARα-/- pericytes. We will also investigate if PPARα regulates mitochondrial biogenesis and function
through the SIRT1/PGC-1α pathway using pericyte-specific SIRT1 KO mice and primary SIRT1-/- pericytes.
These studies will elucidate a novel pathogenic mechanism responsible for mitochondrial damage and
oxidative stress in DR and reveal a new therapeutic strategy for DR. These studies will also contribute to the
understanding of the mechanism underlying therapeutic effects of fenofibrate on re...

## Key facts

- **NIH application ID:** 10543031
- **Project number:** 7R01EY019309-13
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jian-Xing Jay Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,625
- **Award type:** 7
- **Project period:** 2009-03-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543031

## Citation

> US National Institutes of Health, RePORTER application 10543031, A new pathogenic mechanism for diabetic retinopathy (7R01EY019309-13). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10543031. Licensed CC0.

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