Remote Ischemic Preconditioning Protects Retinal Photoreceptors: Evidence From a Rat Model of Light-Induced Photoreceptor Degeneration

Brandli, Alice; Johnstone, Daniel M.; Stone, Jonathan

doi:10.1167/iovs.16-19361

Cited by 18 publications

(12 citation statements)

References 69 publications

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“…One additional translational note: Determining what minimum magnitude, duration, and frequency of systemic hypoxia are required to induce the heritable, adaptive phenotype we report here is of keen interest to us, but our RHC stimulus is not sacrosanct. Other intermittent systemic hypoxia treatments, 18 remote limb conditioning, 44 , 45 or a pharmacological mimic 46 of either that ultimately modulates the expression of these proteins in a similar manner may someday serve as a viable therapeutic for reducing the incidence of ischemic retinopathy.…”

Section: Discussionmentioning

confidence: 99%

Intermittent Hypoxia Promotes Functional Neuroprotection from Retinal Ischemia in Untreated First-Generation Offspring: Proteomic Mechanistic Insights

Harman

Guidry

Gidday

2020

Invest. Ophthalmol. Vis. Sci.

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Purpose Stress can lead to short- or long-term changes in phenotype. Accumulating evidence also supports the transmission of maladaptive phenotypes, induced by adverse stressors, through the germline to manifest in subsequent generations, providing a novel mechanistic basis for the heritability of disease. In the present study in mice, we tested the hypothesis that repeated presentations of a nonharmful conditioning stress, demonstrated previously to protect against retinal ischemia, will also provide ischemic protection in the retinae of their untreated, first-generation (F1) adult offspring. Methods Swiss–Webster ND4 outbred mice were mated following a 16-week period of brief, every-other-day conditioning exposures to mild systemic hypoxia (repetitive hypoxic conditioning, RHC). Retinae of their 5-month-old F1 progeny were subjected to unilateral ischemia. Scotopic electroretinography quantified postischemic outcomes. The injury-resilient retinal proteome was revealed by quantitative mass spectrometry, and bioinformatic analyses identified the biochemical pathways and networks in which these differentially expressed proteins operate. Results Significant resilience to injury in both sexes was documented in F1 mice derived from RHC-treated parents, relative to matched F1 adult progeny derived from normoxic control parents. Ischemia-induced increases and decreases in the expression of many visual transduction proteins that are integral to photoreceptor function were abrogated by parental RHC, providing a molecular basis for the observed functional protection. Conclusions Our proteomic analyses provided mechanistic insights into the molecular manifestation of the inherited, injury-resilient phenotype. To our knowledge, this is the first study in a mammalian model documenting the reprogramming of heritability to promote disease resilience in the next generation.

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Section: Discussionmentioning

confidence: 99%

Intermittent Hypoxia Promotes Functional Neuroprotection from Retinal Ischemia in Untreated First-Generation Offspring: Proteomic Mechanistic Insights

Harman

Guidry

Gidday

2020

Invest. Ophthalmol. Vis. Sci.

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“…Animal models of light-induced retinopathy have been used to study phototoxic retinal damage and associated mechanisms, including oxidative stress responses and metabolic abnormalities [ 31 , 32 , 33 , 34 ]. It was observed that many genes were upregulated in light-damaged retinas of Balb/c mice.…”

Section: Discussionmentioning

confidence: 99%

Lutein and Zeaxanthin Isomers Protect against Light-Induced Retinopathy via Decreasing Oxidative and Endoplasmic Reticulum Stress in BALB/cJ Mice

Yan

Beight

2018

Nutrients

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Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are the major factors underlying photoreceptor degeneration. Lutein, RR-zeaxanthin (3R,3’R-zeaxanthin) and RS (meso)-zeaxanthin (3R,3’S-RS- zeaxanthin) (L/Zi) could protect against cell damage by ameliorating OS in retina. In this study, we examined the effect of L/Zi supplementation in a mouse model of photoreceptor degeneration and investigated whether the treatment of L/Zi ameliorated OS and ERS. BALB/cJ mice after light exposure were used as the animal model. The protective effects of L/Zi were observed by electroretinography (ERG) and terminal deoxyuridine triphosphate nick-end labeling (TUNEL) analysis. The underlying mechanisms related to OS and ERS were explored by Western blotting. After L/Zi treatment, the ERG amplitudes were significantly higher, and the number of TUNEL-positive cells was significantly reduced compared to that of the vehicle group. Western blotting results revealed that OS was ameliorated according to the significant downregulation of phosphorylated c-Jun N-terminal kinase (p-JNK), and significant upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, ERS was reduced according to the significant downregulation of 78 kDa glucose-regulated protein (GRP78), phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), activating transcription factor 4 (ATF4) and activating transcription factor (ATF6). Our data shows that L/Zi provided functional and morphological preservation of photoreceptors against light damage, which is probably related to its mitigation of oxidative and endoplasmic reticulum stress.

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“…While most animal and clinical studies of RIC have focussed on protection against subsequent severe ischemia-reperfusion injury (e.g. ischemic heart disease, acute pre-renal kidney injury, ischemic stroke), there is evidence from animal studies that the beneficial effects of RIC are not confined to ischemic injuries ( Brandli et al, 2016 ; Liu et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Remote tissue conditioning is neuroprotective against MPTP insult in mice

et al. 2018

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Remote Ischemic Preconditioning Protects Retinal Photoreceptors: Evidence From a Rat Model of Light-Induced Photoreceptor Degeneration

Cited by 18 publications

References 69 publications

Intermittent Hypoxia Promotes Functional Neuroprotection from Retinal Ischemia in Untreated First-Generation Offspring: Proteomic Mechanistic Insights

Intermittent Hypoxia Promotes Functional Neuroprotection from Retinal Ischemia in Untreated First-Generation Offspring: Proteomic Mechanistic Insights

Lutein and Zeaxanthin Isomers Protect against Light-Induced Retinopathy via Decreasing Oxidative and Endoplasmic Reticulum Stress in BALB/cJ Mice

Remote tissue conditioning is neuroprotective against MPTP insult in mice

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