Ceruloplasmin/Hephaestin Knockout Mice Model Morphologic and Molecular Features of AMD

Hadziahmetovic, Majda; Dentchev, Tzvete; Song, Ying; Haddad, Nadine; He, Xuming; Hahn, Paul; Praticò, Domenico; Wen, Rong; Harris, Z. Leah; Lambris, John D.; Beard, John L.; Dunaief, Joshua L.

doi:10.1167/iovs.07-1472

Cited by 112 publications

(102 citation statements)

References 44 publications

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“…Mice homozygous for a null mutation in the hemochromatosisassociated gene, Hfe, exhibit late-onset (18 months) RPE hypertrophy and hyperplasia, presumably as a result of iron accumulation (75). Similarly, iron buildup in the RPE of ceruloplasmin/hephaestin double-knockout mice leads to RPE hyperplasia and hypertrophy, with increased autofluorescent deposits in 7- to 9-month-old animals (76). In vivo ribozyme-mediated knockdown of murine manganese superoxide dismutase, which is encoded by the nuclear gene Sod2 and which localizes to the mitochondrial matrix, causes "distended" RPE with vacuoles and autofluorescent aggregates (77).…”

Section: Discussionmentioning

confidence: 99%

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Zhao

Yasumura²,

Li³

et al. 2011

J. Clin. Invest.

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278

285

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Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge is limited regarding the pathways responsible for adult RPE stress responses in vivo. RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration. Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE-characteristic proteins and cellular hypertrophy. The electrical response of the retina to light decreased and photoreceptors eventually degenerated. Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto-oncogene pathway. RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway. Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation. Importantly, treatment with the mTOR inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults. These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress. IntroductionThe retinal pigment epithelium (RPE) is a polarized, cuboidal epithelial cell layer situated in the outer retina between the photoreceptors and choroidal vasculature. The RPE supplies an estimated 60% of the glucose consumed by the neural retina (1) and performs a variety of other functions crucial for retinal homeostasis, including delivery of amino acids and docosahexaenoic acid for photoreceptor protein and membrane synthesis; transport, storage, and enzymatic conversion of retinoids essential for phototransduction; regulation of fluid and ion balance in the subretinal space; maintenance of the blood retinal barrier; secretion of growth factors; and phagocytosis of shed photoreceptor outer segment membranes (2). The RPE is a postmitotic tissue, so RPE cells must carry out these functions for the life of an individual.The retinal degenerative consequences of mutations in RPEexpressed genes illustrate the importance of the RPE for photoreceptor viability in humans. Mutations that impair production of the chromophore 11-cis retinal cause Leber congenital amaurosis, retinitis pigmentosa (RP), and allied disorders (3). Disruption of RPE phagocytosis causes RP and rod/cone dystrophy (4, 5). Mutations that affect ion channel function cause disease of the specialized retinal region necessary for high-acuity vision (the macula) (6) as well as RP (7), while mutations in genes encoding the RPE-secreted proteins TIMP3 (8) and EFEMP1 (9) cause lateronset macular disease.

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Section: Discussionmentioning

confidence: 99%

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Zhao

Yasumura²,

Li³

et al. 2011

J. Clin. Invest.

Self Cite

278

285

View full text Add to dashboard Cite

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“…Ceruloplasmin knockout mice exhibited morphologic and molecular features of agerelated macular degeneration. 23 Furthermore, ceruloplasmin was detected in seven of ten patients with exfoliation syndrome, but in only one of the eight controls. 13 In our study, we did not find a significant difference between patients and controls in terms of ceruloplasmin activity.…”

Section: Discussionmentioning

confidence: 94%

Ceruloplasmin and Catalase Activites in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma

Mumcuoğlu¹,

Demirdöğen²,

Ceylan³

et al. 2013

Turkiye Klinikleri J Med Sci

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A AB BS ST TR RA AC CT T O Ob bj je ec ct ti iv ve e: : Pseudoexfoliation syndrome (PEX) is an age-related systemic disorder primarily with ocular manifestations. PEX is considered as the most common identifiable cause of glaucoma (pseudoexfoliation glaucoma, PEG) and loss of vision. Oxidative stress was suggested to be involved in the pathogenesis of PEX and PEG. Catalase is an antioxidant enzyme which catalyzes decomposition of hydrogen peroxide to water and oxygen. Ceruloplasmin was reported to have antioxidant functions, as well as pro-oxidant activity. This study has aimed to determine whether ceruloplasmin and catalase activities have a role in the development of PEX and/or PEG. M Ma at te er ri ia al l a an nd d M Me et th ho od ds s: : Ceruloplasmin and catalase activities were determined in serum samples of 32 cases of PEX, 30 cases of PEG and 32 control subjects using spectrophotometric methods. R Re es su ul lt ts s: : Ceruloplasmin activities of PEX patients (32.94±16.36 U/L) and PEG patients (29.98±13.15 U/L) were similar and slightly lower than those of controls (35.22±21.32 U/L). However, the differences were not statistically significant. Catalase activites were found to be 61.96±33.95 U/L and 60.44±50.84 U/L in PEX and PEG patients, respectively. Controls had slightly, but insignificantly, higher catalase activities (64.98±58.14 U/L). C Co on nc cl lu us si io on n: : Neither catalase nor ceruloplasmin activities are significantly related with PEX or PEG in the studied Turkish population. As the mean age of populations keeps increasing, PEX may become more common in the future. Therefore, further studies are needed to decipher the pathophysiology of this important disorder.

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“…Furthermore, mice deficient in the ferroxidases ceruloplasmin and hephaestin accumulate iron in the retina and subsequently have retinal degeneration with features of age-related macular degeneration. 2,3 In these mice, iron chelation with the orally absorbed and cellpermeant iron chelator deferiprone (Ferriprox) ameliorated oxidative stress and protected against iron overload-induced retinal degeneration. 4 Because other investigators showed that the iron chelator deferoxamine can protect against retinal light damage and retinal ischemia reperfusion injury, Hadziahmetovic et al 5 decided to test the recently US Food and Drug Administration-approved drug deferiprone because it is orally absorbed and has not been associated with retinal toxic effects in patients or mice.…”

Section: Xidative Stress Has Been Implicatedmentioning

confidence: 99%

Treatment of Oxidative Stress With Chelation Therapy

Zarbin¹

2012

Arch Ophthalmol

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Ceruloplasmin/Hephaestin Knockout Mice Model Morphologic and Molecular Features of AMD

Abstract: DKOs have age-dependent iron accumulation followed by retinal degeneration modeling some of the morphologic and molecular features of AMD. Therefore, these mice are a good platform on which to test therapeutic agents for AMD, such as antioxidants, iron chelators, and antiangiogenic agents.

Cited by 112 publications

References 44 publications

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice

Ceruloplasmin and Catalase Activites in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma

Treatment of Oxidative Stress With Chelation Therapy

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