Mechanism of All-trans-retinal Toxicity with Implications for Stargardt Disease and Age-related Macular Degeneration

Chen, Yu; Okano, Kiichiro; Maeda, Tadao; Chauhan, Vishal; Golczak, Marcin; Maeda, Akiko; Palczewski, Krzysztof

doi:10.1074/jbc.m111.315432

Cited by 198 publications

(233 citation statements)

References 53 publications

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“…Another important source of superoxide generation by photoreceptor cells is NADPH oxidase (19). Interestingly, pharmacologic inhibition of this enzyme also decreased the diabetesinduced generation of superoxide by mouse retina.…”

Section: Discussionmentioning

confidence: 99%

“…Other animals were injected intraperitoneally daily for 2 mo with 36 mg/ kg of apocynin, an NADPH oxidase inhibitor in DMSO as previously reported (19). NADPH oxidase is known to exist in photoreceptor cells, where it has been linked to retinal degeneration (45)(46)(47).…”

Section: Methodsmentioning

confidence: 99%

“…NADPH oxidase is another potential source of superoxide in photoreceptors (19). We administered apocynin, a potent inhibitor of NADPH oxidase (20) for the 2 mo of diabetes to investigate the contribution of NADPH oxidase to retinal superoxide generation in diabetes.…”

Section: Significancementioning

confidence: 99%

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Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Veenstra

Palczewski

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Accumulating evidence suggests that photoreceptor cells play a previously unappreciated role in the development of early stages of diabetic retinopathy, but the mechanism by which this occurs is not clear. Inhibition of oxidative stress is known to inhibit the vascular lesions of early diabetic retinopathy, and we investigated whether the diabetes-induced oxidative stress in the retina emanates from photoreceptors. Superoxide generation was assessed in retinas of male C57BL/6J mice made diabetic for 2 mo (4 mo of age when killed) using histochemical (dichlorofluorescein and dihydroethidine) and bioluminescence (lucigenin) methods. Photoreceptors were eliminated in vivo by genetic (opsin −/− ) and chemical (iodoacetic acid) techniques. Immunoblots were used to measure expression of intercellular adhesion molecule 1 and the inducible form of nitric oxide synthase. Diabetes increased the generation of superoxide by diabetic mouse retina more at night than during the day. Photoreceptors were the major source of reactive oxygen species in the retina, and their deletion (either genetically in opsin −/− mice or acutely with iodoacetic acid) inhibited the expected diabetes-induced increase in superoxide and inflammatory proteins in the remaining retina. Both mitochondria and NADPH oxidase contributed to the observed retinal superoxide generation, which could be inhibited in vivo with either methylene blue or apocynin. Photoreceptors are the major source of superoxide generated by retinas of diabetic mice. Pharmaceuticals targeting photoreceptor oxidative stress could offer a unique therapy for diabetic retinopathy.T he pathogenesis of diabetic retinopathy remains unclear, but prior work by us and others has provided strong evidence in animal models that oxidative stress and inflammatory processes play important roles in the development of the vascular lesions characteristic of early stages of this retinopathy (1, 2). Inhibition of oxidative stress by feeding antioxidants or overexpressing antioxidant enzymes has reduced diabetes-induced degeneration of retinal capillaries (3-7). Moreover, oxidative stress has been reported to regulate expression of proinflammatory proteins (8-10), which also have been shown to play a critical role in the pathogenesis of this early retinopathy (2). However, which cells of the retina are the major sources of such oxidative stress in diabetes is unclear. In vitro studies of retinal endothelial cells or Müller cells incubated in elevated levels of glucose have demonstrated that these cells can contribute to oxidative stress (11, 12), but the contribution of other cell types and their relative importance has not been studied.Rod and cone photoreceptor cells are the most prevalent cells in the retina. These postmitotic cells have a very high metabolic rate, using more oxygen than other cells throughout the body. They are also considered as likely contributors to the eventual development of retinal hypoxia and subsequent neovascularization in advanced stages of diabetic retinopathy (13,14). Th...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Veenstra

Palczewski

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The primary cause of acute retinal degeneration after bright light exposure in Abca4 −/− Rdh8 −/− mice is the delayed clearance of atRAL from photoreceptors (18). Moreover, light-induced retinal degeneration in Abca4 −/− Rdh8 −/− mice can be prevented by pharmacological interventions such as the retinoid cycle inhibitor with a primary amino group, retinylamine (12,30), and the NAPDH oxidase inhibitor, apocynin (31,(47)(48)(49) (Fig. S3).…”

Section: Photoreceptor Cell Apoptosis Is Caused By Atral In Neural Rementioning

confidence: 98%

“…The Abca4 −/− Rdh8 −/− mouse also exhibits slowly progressive retinal degeneration under normal lighting conditions with a phenotype similar to AMD that responds to the above treatments (29). Downstream consequences of atRAL-induced cellular toxicity have also been studied, and pharmacologic inhibition of certain downstream targets can prevent atRAL-induced cell death (31).…”

mentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Atrophic age-related and juvenile macular degeneration are especially devastating due to lack of an effective cure. Two retinal cell types, photoreceptor cells and the adjacent retinal pigmented epithelium (RPE), reportedly display the earliest pathological changes. Abca4 −/− Rdh8 −/− mice, which mimic many features of human retinal degeneration, allowed us to determine the sequence of light-induced events leading to retinal degeneration. Using two-photon microscopy with 3D reconstruction methodology, we observed an initial strong retinoid-derived fluorescence and expansion of Abca4 −/− Rdh8 −/− mouse rod cell outer segments accompanied by macrophage infiltration after brief exposure of the retina to bright light. Additionally, light-dependent fluorescent compounds produced in rod outer segments were not transferred to the RPE of mice genetically defective in RPE phagocytosis. Collectively, these findings suggest that for light-induced retinopathies in mice, rod photoreceptors are the primary site of toxic retinoid accumulation and degeneration, followed by secondary changes in the RPE.

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Retinoids and the Visual Cycle

Babino

Lintig

2015

The Retinoids

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Mechanism of All-trans-retinal Toxicity with Implications for Stargardt Disease and Age-related Macular Degeneration

Cited by 198 publications

References 53 publications

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Retinoids and the Visual Cycle

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