Nrf2 activation is a potential therapeutic approach to attenuate diabetic retinopathy

Devy Deliyanti, Saeed F. Alrashdi, Sih Min Tan, Colin Meyer, Keith W. Ward, Judy B. de Haan, Jennifer L. Wilkinson-Berka

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

PURPOSE. Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the blood-retinal barrier (BRB) and associated damage to macroglial Müller cells. METHODS. Sprague-Dawley rats were randomized to become diabetic or nondiabetic and administered dh404 by gavage for 10 weeks. Complementary in vitro studies were performed in cultured Müller cells exposed to hyperglycemia. RESULTS. In diabetes, dh404 prevented vascular leakage into the retina and vitreous cavity as well as upregulation of the vascular permeability and angiogenic factors, VEGF, and angiopoietin-2, and inflammatory mediators, including TNF-α and IL-6. Müller cells, which maintain BRB integrity and become gliotic in diabetes with increased immunolabeling for glial fibrillary acidic protein, were protected by dh404. In diabetes, dh404 bolstered the antioxidant capacity of the retina with an increase in hemeoxygenase-1, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) quinine oxidoreductase- 1, and Nrf2. Further, dh404 attenuated the diabetes-induced increase in oxidative stress as measured by dihydroethidium and 8-oxo-20'-deoxyguanosine (8-OHdG) immunolabeling as well as NADPH oxidase isoform expression. Studies in Müller cells supported these findings with dh404 attenuating the hyperglycemia-induced increase in vascular permeability, angiogenic and inflammatory mediators, and oxidative stress. CONCLUSIONS. Our data demonstrate the ability of dh404 to protect the retina against diabetesinduced damage and potentially prevent vision loss.

Original languageEnglish
Pages (from-to)815-825
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • Diabetic retinopathy
  • Müller cells
  • Nrf2
  • Oxidative stress

Cite this

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title = "Nrf2 activation is a potential therapeutic approach to attenuate diabetic retinopathy",
abstract = "PURPOSE. Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the blood-retinal barrier (BRB) and associated damage to macroglial M{\"u}ller cells. METHODS. Sprague-Dawley rats were randomized to become diabetic or nondiabetic and administered dh404 by gavage for 10 weeks. Complementary in vitro studies were performed in cultured M{\"u}ller cells exposed to hyperglycemia. RESULTS. In diabetes, dh404 prevented vascular leakage into the retina and vitreous cavity as well as upregulation of the vascular permeability and angiogenic factors, VEGF, and angiopoietin-2, and inflammatory mediators, including TNF-α and IL-6. M{\"u}ller cells, which maintain BRB integrity and become gliotic in diabetes with increased immunolabeling for glial fibrillary acidic protein, were protected by dh404. In diabetes, dh404 bolstered the antioxidant capacity of the retina with an increase in hemeoxygenase-1, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) quinine oxidoreductase- 1, and Nrf2. Further, dh404 attenuated the diabetes-induced increase in oxidative stress as measured by dihydroethidium and 8-oxo-20'-deoxyguanosine (8-OHdG) immunolabeling as well as NADPH oxidase isoform expression. Studies in M{\"u}ller cells supported these findings with dh404 attenuating the hyperglycemia-induced increase in vascular permeability, angiogenic and inflammatory mediators, and oxidative stress. CONCLUSIONS. Our data demonstrate the ability of dh404 to protect the retina against diabetesinduced damage and potentially prevent vision loss.",
keywords = "Diabetic retinopathy, M{\"u}ller cells, Nrf2, Oxidative stress",
author = "Devy Deliyanti and Alrashdi, {Saeed F.} and Tan, {Sih Min} and Colin Meyer and Ward, {Keith W.} and {de Haan}, {Judy B.} and Wilkinson-Berka, {Jennifer L.}",
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Nrf2 activation is a potential therapeutic approach to attenuate diabetic retinopathy. / Deliyanti, Devy; Alrashdi, Saeed F.; Tan, Sih Min; Meyer, Colin; Ward, Keith W.; de Haan, Judy B.; Wilkinson-Berka, Jennifer L.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 2, 01.02.2018, p. 815-825.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Nrf2 activation is a potential therapeutic approach to attenuate diabetic retinopathy

AU - Deliyanti, Devy

AU - Alrashdi, Saeed F.

AU - Tan, Sih Min

AU - Meyer, Colin

AU - Ward, Keith W.

AU - de Haan, Judy B.

AU - Wilkinson-Berka, Jennifer L.

PY - 2018/2/1

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N2 - PURPOSE. Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the blood-retinal barrier (BRB) and associated damage to macroglial Müller cells. METHODS. Sprague-Dawley rats were randomized to become diabetic or nondiabetic and administered dh404 by gavage for 10 weeks. Complementary in vitro studies were performed in cultured Müller cells exposed to hyperglycemia. RESULTS. In diabetes, dh404 prevented vascular leakage into the retina and vitreous cavity as well as upregulation of the vascular permeability and angiogenic factors, VEGF, and angiopoietin-2, and inflammatory mediators, including TNF-α and IL-6. Müller cells, which maintain BRB integrity and become gliotic in diabetes with increased immunolabeling for glial fibrillary acidic protein, were protected by dh404. In diabetes, dh404 bolstered the antioxidant capacity of the retina with an increase in hemeoxygenase-1, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) quinine oxidoreductase- 1, and Nrf2. Further, dh404 attenuated the diabetes-induced increase in oxidative stress as measured by dihydroethidium and 8-oxo-20'-deoxyguanosine (8-OHdG) immunolabeling as well as NADPH oxidase isoform expression. Studies in Müller cells supported these findings with dh404 attenuating the hyperglycemia-induced increase in vascular permeability, angiogenic and inflammatory mediators, and oxidative stress. CONCLUSIONS. Our data demonstrate the ability of dh404 to protect the retina against diabetesinduced damage and potentially prevent vision loss.

AB - PURPOSE. Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the blood-retinal barrier (BRB) and associated damage to macroglial Müller cells. METHODS. Sprague-Dawley rats were randomized to become diabetic or nondiabetic and administered dh404 by gavage for 10 weeks. Complementary in vitro studies were performed in cultured Müller cells exposed to hyperglycemia. RESULTS. In diabetes, dh404 prevented vascular leakage into the retina and vitreous cavity as well as upregulation of the vascular permeability and angiogenic factors, VEGF, and angiopoietin-2, and inflammatory mediators, including TNF-α and IL-6. Müller cells, which maintain BRB integrity and become gliotic in diabetes with increased immunolabeling for glial fibrillary acidic protein, were protected by dh404. In diabetes, dh404 bolstered the antioxidant capacity of the retina with an increase in hemeoxygenase-1, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) quinine oxidoreductase- 1, and Nrf2. Further, dh404 attenuated the diabetes-induced increase in oxidative stress as measured by dihydroethidium and 8-oxo-20'-deoxyguanosine (8-OHdG) immunolabeling as well as NADPH oxidase isoform expression. Studies in Müller cells supported these findings with dh404 attenuating the hyperglycemia-induced increase in vascular permeability, angiogenic and inflammatory mediators, and oxidative stress. CONCLUSIONS. Our data demonstrate the ability of dh404 to protect the retina against diabetesinduced damage and potentially prevent vision loss.

KW - Diabetic retinopathy

KW - Müller cells

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KW - Oxidative stress

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