NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa

Usui, Shinichi; Oveson, Brian C.; Lee, Sun Young; Jo, Yeonhwa; Yoshida, Tomoo; Miki, Akiko; Miki, Katsuaki; Iwase, Takeshi; Lü, Lili; Campochiaro, Peter A.

doi:10.1111/j.1471-4159.2009.06195.x

Cited by 118 publications

(95 citation statements)

References 50 publications

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“…The death of rods is inevitably followed by cone cell death, caused mainly by oxidative damage (36,37). Usui et al reported that generation of excessive ROS caused oxidative damage to cones in the retinal degeneration-1 (rd1+/+) mouse, a model of retinitis pigmentosa (38). A mixture of antioxidants, including α-tocopherol, ascorbic acid, Mn (III) tetrakis (4-benzoic acid) porphyrin, and α-lipoic acid, reduced cone cell death in these rd1+/+ mice (36).…”

Section: Discussionmentioning

confidence: 99%

Role of Oxidative Stress in Retinal Photoreceptor Cell Death in N-Methyl-N-nitrosourea–Treated Mice

et al. 2012

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Abstract. This study aimed to investigate whether oxidative stress contributes to retinal cell death in a mouse model of photoreceptor degeneration induced by N-methyl-N-nitrosourea (MNU). We measured in vitro MNU-induced radical production in retinal cell cultures of murine 661W photoreceptor-derived cells; RGC-5, a mouse ganglion cell line; and primary retinal cells. The addition of MNU induced oxidative radical generation in 661W and primary retinal cells, but not in RGC-5 cells. Edaravone, a free radical scavenger, at 1 μM reduced MNU-induced radical production in 661W and primary retinal cells. To induce in vivo retinal photoreceptor degeneration in mice, we administered 60 mg/kg MNU by intraperitoneal injection. We intravenously administered 1 mg/kg edaravone immediately and at 6 h after the MNU injection. Retinal photoreceptor degeneration was evaluated by measuring the thickness of the outer nuclear layer (ONL) by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and by oxidative stress markers. MNU caused photoreceptor cell loss at 7 days after administration. Edaravone inhibited ONL thinning and reduced TUNEL-positive cells and the oxidative stress markers. These findings indicate that MNU leads to selective photoreceptor degradation via oxidative stress in vitro and in vivo and may help to understand the pathogenic mechanism of retinitis pigmentosa.

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Section: Discussionmentioning

confidence: 99%

Role of Oxidative Stress in Retinal Photoreceptor Cell Death in N-Methyl-N-nitrosourea–Treated Mice

et al. 2012

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“…Significant cone ERG responses were not detected in eupatilin-injected rd16 mice at P30 (not shown). Oxidative damage has been suggested as a major contributing factor to cone cell death following the death of rod cells (35). Thus, it is likely that the diminished effect of eupatilin at P30 was due to the secondary death of cone cells.…”

Section: This Suggests That Although Eupatilin Can Promote Ciliogenesmentioning

confidence: 99%

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

Kim¹,

Kim²,

Jung³

et al. 2018

Journal of Clinical Investigation

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“…NADPH oxidase is known to exist in photoreceptor cells, where it has been linked to retinal degeneration (45)(46)(47). Administration of both agents commenced 1 wk after the onset of diabetes to assure that drug treatment did not influence the severity of diabetes.…”

Section: Methodsmentioning

confidence: 99%

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.

287

285

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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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NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa

Cited by 118 publications

References 50 publications

Role of Oxidative Stress in Retinal Photoreceptor Cell Death in N-Methyl-N-nitrosourea–Treated Mice

Role of Oxidative Stress in Retinal Photoreceptor Cell Death in N-Methyl-N-nitrosourea–Treated Mice

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

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

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