Continuous exposure to non-lethal doses of sodium iodate induces retinal pigment epithelial cell dysfunction

Zhang, Xiaoyu; Ng, Tsz Kin; Brelén, Mårten; Wu, Di; Wang, Jian Xiong; Chan, Kwok Ping; Yung, Jasmine Sum Yee; Cao, Di; Wang, Yumeng; Zhang, Shaodan; Chan, Sun On; Pang, Chi Pui

doi:10.1038/srep37279

Cited by 33 publications

(32 citation statements)

References 42 publications

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“…5). We have previously demonstrated that phagocytosed beads would show yellow fluorescence signal and those not phagocytosed would be in green signal 22 . After 5-day nicotine and cotinine treatment, the phagocytotic activity of rat RPE cells on rat POS was significantly reduced in 1 μM nicotine (46.43% phagocytosed beads; p < 0.001), 1 μM cotinine (62.59% phagocytosed beads; p < 0.001), 2 μM cotinine (67.09% phagocytosed beads; p < 0.001) and 2 μM nicotine-cotinine treatments (69.23% phagocytosed beads; p < 0.01), compared to the vehicle control (92.18% phagocytosed beads).…”

Section: Resultsmentioning

confidence: 98%

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Disruption of retinal pigment epithelial cell properties under the exposure of cotinine

Zhang

Brelén

et al. 2017

Sci Rep

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Cigarette smoking is a major risk factor for age-related macular degeneration (AMD), in which progressive retinal pigment epithelial (RPE) cell degeneration is a major pathological change. Nicotine is a major biologically active component in cigarette smoke. It is continuously catabolized into cotinine, which has longer half-life and higher concentration in tissue cells and fluids. Here we hypothesized that continuous exposure of cotinine has more potent effects on human RPE cell properties than nicotine. Human RPE cell line (ARPE-19) was treated continuously with 1–2 µM of nicotine and/or cotinine for 7 days. RPE cells treated with 2 μM cotinine and nicotine-cotinine mixture has lower MTT signals without significant changes in cell apoptosis or integrity. Moreover, RPE cell migration was retarded under cotinine treatments, but not nicotine. Both nicotine and cotinine treatments attenuated the phagocytotic activity of RPE cells. In addition, cotinine and nicotine-cotinine mixture suppressed VEGF and IL-8 expression and upregulated TIMP-2 expression. Expressions of autophagy genes were upregulated by the cotinine treatment, whereas expressions of epithelial-to-mesenchymal transition markers were downregulated. In conclusion, our study, for the first time, demonstrated that cotinine, rather than nicotine, affects the properties of RPE cells in vitro, which could explain the smoking-induced RPE pathology.

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Section: Resultsmentioning

confidence: 98%

“…RPE explant culture was used to evaluate the phagocytotic activity of RPE cells ex vivo 22 . Briefly, Sprague Dawley (SD) rats, aged 6–8 weeks, were enucleated and dissected.…”

Section: Methodsmentioning

confidence: 99%

Disruption of retinal pigment epithelial cell properties under the exposure of cotinine

Zhang

Brelén

et al. 2017

Sci Rep

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“…19,41 Recent studies in cell cultures of ARPE-19 further show that exposure to sublethal doses of SI retard RPE cell migration and cause reduced expression of the cell junction protein ZO-1. 42 Taken together, these processes probably underlie the rapid formation of retinal edema following SI administration as detected by OCT and histology. The formation and resolution of such edema caused by the early toxicity of SI may explain the observed initial OKT loss followed by partial recovery at 1 week.…”

Section: Discussionmentioning

confidence: 99%

Course of Sodium Iodate–Induced Retinal Degeneration in Albino and Pigmented Mice

Chowers

Cohen

Marks-Ohana

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To characterize the course of sodium iodate (SI)-induced retinal degeneration in young adult albino and pigmented mice. (25, 50, and 100 mg/kg) were performed in 7-to 8-week-old BALB/c and C57Bl/6J mice. Retinal function and structure was assessed at baseline, 24 hours, 3 days, 1, 2, 3, and 4 weeks postinjection by optokinetic tracking response, ERG, optical coherence tomography (OCT), and histologic and immunohistochemical techniques. METHODS. Single intraperitoneal (IP) injections of SI RESULTS.The 50 mg/kg SI dosage was selected after dose ranging due to consistent retinal effects and lack of systemic toxicity. Time-dependent deterioration in retinal function and morphology was consistently observed between 1 and 4 weeks in all measured parameters. These include reduction of ERG responses, thinning of retinal layers as observed by OCT and histology, and loss of RPE nuclei. Immunohistochemistry revealed rapid RPE disorganization with loss of tight junctions and markedly reduced expression of RPE65 and rod opsin, accompanied by mislocalization of cone opsins. Earlier time points displayed variable results, including partial recovery of visual acuity at 1 week and supranormal ERG cone responses at 24 hours, suggesting possible limitations of early intervention and assessment in the SI model. CONCLUSIONS.A single IP injection of 50 mg/kg SI leads to severe RPE injury followed by vision impairment, dysfunction, and loss of photoreceptors in both BALB/c and C57Bl/6J mice. This easily induced and reproducible noninherited model may serve as a useful tool for seeking and evaluating novel therapeutic modalities for the treatment of retinal degenerations caused by primary failure of the RPE.Keywords: sodium iodate, RPE toxicity, retinal degeneration, mouse model D iseases such as AMD, Best disease, and subtypes of retinitis pigmentosa RP are major causes of visual disability. 1 In these diseases, primary dysfunction, degeneration, and loss of the RPE ultimately results in secondary death of photoreceptors, leading to visual loss. [2][3][4] Despite certain progress in the treatment of retinal degeneration, it remains an essentially irreversible process in which many patients eventually lose their sight. Animal models provide an invaluable tool for searching and testing of novel therapeutic modalities. Animals carrying natural mutations (usually in one gene) provide well-established models for inherited retinal diseases. 5,6 However, the pathogenesis of multifactorial retinal degenerations such as AMD involves complex genetic and environmental factors, leading to expression of disease at older ages. 7 The majority of geneticallyinherited animal models of ocular disease do not entirely mimic such conditions because of early disease onset and progression. 8 Regardless of etiology, maintaining proper RPE function is a major therapeutic target in these diseases, and currently pharmaceutical, genetic, and cellular approaches are being tested to this end in a variety of in vitro and in vivo models, as well as in clini...

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“…Besides using amyloid beta 1-40 oligomers, oxidative stress upon RPE cells may also resemble AMD conditions in vitro. Studies showed that a low dose of sodium iodate significantly decreased phagocytotic activity, cellular acidity, and autophagy, leading to RPE cell degeneration [ 54 , 55 ], while a high dosage of sodium iodate increased the expression of pentraxin 3, thereby accelerating RPE cell death [ 56 ]. Another in vitro model was the application of tert -butyl hydroperoxide on human fetal RPE and APRE-19 cells [ 57 ].…”

Section: Disease Mechanisms Of Amdmentioning

confidence: 99%

Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration?

Yang

Lam

2020

IJMS

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Age-related macular degeneration (AMD) is a leading cause of severe visual loss among the elderly. AMD patients are tormented by progressive central blurring/loss of vision and have limited therapeutic options to date. Drusen accumulation causing retinal pigment epithelial (RPE) cell damage is the hallmark of AMD pathogenesis, in which oxidative stress and inflammation are the well-known molecular mechanisms. However, the underlying mechanisms of how RPE responds when exposed to drusen are still poorly understood. Programmed cell death (PCD) plays an important role in cellular responses to stress and the regulation of homeostasis and diseases. Apart from the classical apoptosis, recent studies also discovered novel PCD pathways such as pyroptosis, necroptosis, and ferroptosis, which may contribute to RPE cell death in AMD. This evidence may yield new treatment targets for AMD. In this review, we summarized and analyzed recent advances on the association between novel PCD and AMD, proposing PCD’s role as a therapeutic new target for future AMD treatment.

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Continuous exposure to non-lethal doses of sodium iodate induces retinal pigment epithelial cell dysfunction

Cited by 33 publications

References 42 publications

Disruption of retinal pigment epithelial cell properties under the exposure of cotinine

Disruption of retinal pigment epithelial cell properties under the exposure of cotinine

Course of Sodium Iodate–Induced Retinal Degeneration in Albino and Pigmented Mice

Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration?

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