Role of Sirtuins in Retinal Function Under Basal Conditions

Lin, Jonathan B.; Kubota, Shunsuke; Mostoslavsky, Raúl; Apte, Rajendra S.

doi:10.1007/978-3-319-75402-4_68

Cited by 11 publications

(7 citation statements)

References 20 publications

(22 reference statements)

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“…Therefore, we further analyzed the effects of SIRT4 gene deletion on the structure and function of MGCs and the retina. The loss of SIRT4 had no significant effect on retinal structure or electrophysiological function under basal conditions, which was consistent with the results of Lin et al (2018). Three reasons may explained this situation.…”

Section: Discussionsupporting

confidence: 90%

SIRT4 Is Highly Expressed in Retinal Müller Glial Cells

Wei

Qin

et al. 2022

Front. Neurosci.

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Sirtuin 4 (SIRT4) is one of seven mammalian sirtuins that possesses ADP-ribosyltransferase, lipoamidase and deacylase activities and plays indispensable role in metabolic regulation. However, the role of SIRT4 in the retina is not clearly understood. The purpose of this study was to explore the location and function of SIRT4 in the retina. Therefore, immunofluorescence was used to analyze the localization of SIRT4 in rat, mouse and human retinas. Western blotting was used to assess SIRT4 and glutamine synthetase (GS) protein expression at different developmental stages in C57BL/6 mice retinas. We further analyzed the retinal structure, electrophysiological function and the expression of GS protein in SIRT4-deficient mice. Excitotoxicity was caused by intravitreal injection of glutamate (50 nmol) in mice with long-term intraperitoneal injection of resveratrol (20 mg/Kg), and then retinas were subjected to Western blotting and paraffin section staining to analyze the effect of SIRT4 on excitotoxicity. We show that SIRT4 co-locates with Müller glial cell markers (GS and vimentin). The protein expression pattern of SIRT4 was similar to that of GS, and both increased with development. There were no significant retinal structure or electrophysiological function changes in 2-month SIRT4-deficient mice, while the expression of GS protein was decreased. Moreover, long-term administration of resveratrol can upregulate the expression of SIRT4 and GS while reducing the retinal injury caused by excessive glutamate. These results suggest that SIRT4 is highly expressed in retinal Müller glial cells and is relevant to the expression of GS. SIRT4 does not appear to be essential in retinal development, but resveratrol, as an activator of SIRT4, can upregulate GS protein expression and protect the retina from excitotoxicity.

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Section: Discussionsupporting

confidence: 90%

SIRT4 Is Highly Expressed in Retinal Müller Glial Cells

Wei

Qin

et al. 2022

Front. Neurosci.

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“…The former could be caused by chronic inflammation with enhanced oxidative stress and/or increased inflammatory cytokines, whereas the latter could be caused by increased DNA damage. As a consequence, NAD + levels decrease with age in multiple tissues, including adipose tissue, skeletal muscle, liver, pancreas, skin, neurosensory retina, and brain (Cantó et al, 2015;Lin et al, 2018;Rajman et al, 2018;Verdin, 2015;Yoshino et al, 2018). The realization of such systemic NAD + decline as a fundamental event for age-associated pathophysiology has now provided a strong rationale to develop effective anti-aging interventions using key NAD + intermediates, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) (Rajman et al, 2018;Yoshino et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice

et al. 2019

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“…2 ), allowed increased or maintained retinal metabolic capacity that contributed to protection. 55 Additionally, maintaining NAD + levels may have permitted continued activity of enzymes for which NAD + is a substrate and that have been shown to be critical to retinal health or function (e.g., sirtuins, 5 , 9 , 56 – 58 poly[ADP-ribose] polymerases, 9 , 59 isocitrate dehydrogenases 60 ). For instance, maintaining NAD + levels by treating with NR may allow continued enzyme-mediated DNA repair, which may underlie the observed prevention of accumulation of DNA damage ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Systemic Treatment With Nicotinamide Riboside Is Protective in a Mouse Model of Light-Induced Retinal Degeneration

Zhang

Henneman

Girardot

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Maintaining levels of nicotinamide adenine dinucleotide (NAD +), a coenzyme critical for cellular energetics and biosynthetic pathways, may be therapeutic in retinal disease because retinal NAD + levels decline during retinal damage and degeneration. The purpose of this study was to investigate whether systemic treatment with nicotinamide riboside (NR), a NAD + precursor that is orally deliverable and well-tolerated by humans, is protective in a mouse model of light-induced retinal degeneration. METHODS. Mice were injected intraperitoneally with vehicle or NR the day before and the morning of exposure to degeneration-inducing levels of light. Retinal function was assessed by electroretinography and in vivo retinal morphology and inflammation was assessed by optical coherence tomography. Post mortem retina sections were assessed for morphology, TUNEL, and inflammatory markers Iba1 and GFAP. Retinal NAD + levels were enzymatically assayed. RESULTS. Exposure to degeneration-inducing levels of light suppressed retinal NAD + levels. Mice undergoing light-induced retinal degeneration exhibited significantly suppressed retinal function, severely disrupted photoreceptor cell layers, and increased apoptosis and inflammation in the outer retina. Treatment with NR increased levels of NAD + in retina and prevented these deleterious outcomes. CONCLUSIONS. This study is the first to report the protective effects of NR treatment in a mouse model of retinal degeneration. The positive outcomes, coupled with human tolerance to NR dosing, suggest that maintaining retinal NAD + via systemic NR treatment should be further explored for clinical relevance.

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Role of Sirtuins in Retinal Function Under Basal Conditions

Cited by 11 publications

References 20 publications

SIRT4 Is Highly Expressed in Retinal Müller Glial Cells

SIRT4 Is Highly Expressed in Retinal Müller Glial Cells

Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice

Systemic Treatment With Nicotinamide Riboside Is Protective in a Mouse Model of Light-Induced Retinal Degeneration

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