# Inhibition of HMGB1 as a protective mechanism against diabetic retinopathy

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $447,387

## Abstract

Diabetic retinopathy remains the leading cause of vision loss in working age adults. Previous research
has led to the development of anti-VEGF therapy, which is an effective treatment for proliferative
diabetic retinopathy and macular edema in some patients, while other patients are unresponsive. For
treatment of non-proliferative diabetic retinopathy, few options are available save good glycemic control,
which is problematic for many patients. Recent discoveries offer new insights into the molecular
mechanisms underlying diabetic retinopathy and suggest that in addition to oxidative stress, increased
inflammation may be a major causative factor in diabetes-induced retinal damage. We recently reported
that high glucose significantly increased high mobility group box 1 (HMGB1) protein levels, suggesting a
potential role for the alarmin system in regulating retinal responses to high glucose. HMGB1 is
extensively involved in inflammation; it can serve as a chaperone to regulate transcription in the nucleus,
is secreted by immune cells, interacts with p53, and activates cytokine release. As such, it provides a
promising target to blunt the inflammatory response in the retina. Due to its multiple mechanisms of
activation and roles in various cell types, an improved understanding of the cellular regulation of HMGB1
actions in the retina becomes increasingly important. Our preliminary data demonstrate that insulin-like
growth factor binding protein 3 (IGFBP-3) can inhibit high glucose-induced increases in HMGB1 levels
in retinal endothelial cells (REC). We have previously reported that IGFBP-3 KO mice have retinal
damage similar to rodent models of diabetic retinopathy, despite normal glucose levels. In addition to
IGFBP-3, studies have shown that PKA can directly phosphorylate the Box A region of yeast HMGB1
leading to decreased HMGB1 actions. Studies also showed that increased SIRT1 promoted deacetylation
of HMGB1, leading to reduced cytoplasmic translocation. Thus, there is scientific rationale to investigate
the regulation of HMGB1 by PKA, Epac1, IGFBP-3, and SIRT1. Furthermore, inhibition of HMGB1
activity using an inhibitor (glycyrrhizin) restored retinal thickness and reduced retinal degenerate
capillaries in an in vivo model of retinal ischemia/reperfusion injury in mice. These data have led to the
hypothesis that inhibition of HMGB1 activity in the retina protects against diabetes-induced damage. Our
overall goal is to determine the mechanisms by which the PKA and Epac1 pathways inhibit
HMGB1/inflammation-induced retinal injury and serve as protective pathways that may block diabetic
retinal damage.

## Key facts

- **NIH application ID:** 9899993
- **Project number:** 5R01EY028442-03
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Jena J Steinle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $447,387
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899993

## Citation

> US National Institutes of Health, RePORTER application 9899993, Inhibition of HMGB1 as a protective mechanism against diabetic retinopathy (5R01EY028442-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9899993. Licensed CC0.

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