Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration

Wang, Wenqiu; Gawlik, Katarzyna; Lopez, Joe; Wen, Cindy; Wu, Frances; Shi, William Y.; Scheibler, Samuel; Cai, Huimin; Vairavan, Ram; Shi, Alexander; Haw, Weldon W; Ferreyra, Henry; Zhang, Ming; Chang, Sherman; Zhang, Kang

doi:10.1038/sigtrans.2016.16

Cited by 18 publications

(5 citation statements)

References 25 publications

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“…As a complex disease, AMD is a result of the interplay of aging, environmental factors and genetic factors [ 25 , 26 ]. HTRA1 is one of the most significant susceptibility genes in AMD [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration

Liu

Han

et al. 2023

Cell Commun Signal

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Background Age-related macular degeneration (AMD), characterized by the degeneration of retinal pigment epithelium (RPE) and photoreceptors, is the leading cause of irreversible vision impairment among the elderly. RPE senescence is an important contributor to AMD and has become a potential target for AMD therapy. HTRA1 is one of the most significant susceptibility genes in AMD, however, the correlation between HTRA1 and RPE senescence hasn’t been investigated in the pathogenesis of AMD. Methods Western blotting and immunohistochemistry were used to detect HTRA1 expression in WT and transgenic mice overexpressing human HTRA1 (hHTRA1-Tg mice). RT-qPCR was used to detect the SASP in hHTRA1-Tg mice and ARPE-19 cells infected with HTRA1. TEM, SA-β-gal was used to detect the mitochondria and senescence in RPE. Retinal degeneration of mice was investigated by fundus photography, FFA, SD-OCT and ERG. The RNA-Seq dataset of ARPE-19 cells treated with adv-HTRA1 versus adv-NC were analyzed. Mitochondrial respiration and glycolytic capacity in ARPE-19 cells were measured using OCR and ECAR. Hypoxia of ARPE-19 cells was detected using EF5 Hypoxia Detection Kit. KC7F2 was used to reduce the HIF1α expression both in vitro and in vivo. Results In our study, we found that RPE senescence was facilitated in hHTRA1-Tg mice. And hHTRA1-Tg mice became more susceptible to NaIO3 in the development of oxidative stress-induced retinal degeneration. Similarly, overexpression of HTRA1 in ARPE-19 cells accelerated cellular senescence. Our RNA-seq revealed an overlap between HTRA1-induced differentially expressed genes associated with aging and those involved in mitochondrial function and hypoxia response in ARPE-19 cells. HTRA1 overexpression in ARPE-19 cells impaired mitochondrial function and augmented glycolytic capacity. Importantly, upregulation of HTRA1 remarkably activated HIF-1 signaling, shown as promoting HIF1α expression which mainly located in the nucleus. HIF1α translation inhibitor KC7F2 significantly prevented HTRA1-induced cellular senescence in ARPE-19 cells, as well as improved the visual function in hHTRA1-Tg mice treated with NaIO3. Conclusions Our study showed elevated HTRA1 contributes to the pathogenesis of AMD by promoting cellular senescence in RPE through damaging mitochondrial function and activating HIF-1 signaling. It also pointed out that inhibition of HIF-1 signaling might serve as a potential therapeutic strategy for AMD.

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Section: Discussionmentioning

confidence: 99%

Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration

Liu

Han

et al. 2023

Cell Commun Signal

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“…Environmental factors, including smoking, diet, and possibly sunlight exposure, have been shown to contribute to the risk and progression of retinal diseases such as AMD, likely by increasing oxidative stress ( Ersoy et al., 2014 ; Wang et al., 2016 ). Light-induced retinal degeneration (LIRD) is a rapid and aggressive method to induce retinal degeneration ( Wenzel et al., 2005 ) partly through the generation of oxidative stress ( Nakanishi et al., 2013 ), photoreceptor apoptosis ( Belmonte et al., 2006 ), and/or inflammation in the retina ( Hadziahmetovic et al., 2012 ).…”

Section: Resultsmentioning

confidence: 99%

Utility of the DHFR-based destabilizing domain across mouse models of retinal degeneration and aging

et al. 2022

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“…Over the 12-month review period all progressor regions, including the fellow eye, displayed a greater magnitude of decline in sensitivity in comparison to the nonprogressor eyes, suggestive that collectively the progressors possessed factors, which lead to accelerated impairment of function. The development and progression of AMD is a multifactorial process, but understanding which variables contribute the greatest predilection toward developing late disease has not been definitively established 52–54. Further investigation of the subset of individuals noted to display hastened impairment of function using microperimetry, may allow for greater insight into factors involved with AMD pathogenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

Presymptomatic Retinal Sensitivity Changes in Intermediate Age-Related Macular Degeneration Associated With New Retinal Fluid

Wightman

Abbott

McGuinness

et al. 2019

Trans. Vis. Sci. Tech.

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PurposeTo determine whether change in retinal sensitivity in areas with subretinal or intraretinal fluid secondary to age-related macular degeneration (AMD) precedes visual symptoms. If confirmed, retinal sensitivity testing could be used for home monitoring in AMD.MethodsIndividuals with intermediate AMD enrolled in a longitudinal study were seen every 6 months and underwent best-corrected visual acuity testing (BCVA), spectral domain–optical coherence tomography (SD-OCT), and microperimetry. Asymptomatic individuals who developed incidental, reading center–determined retinal fluid detected on SD-OCT were identified. The point-wise sensitivity (PWS) at the time of fluid detection was compared with 6 and 12 months prior.ResultsFourteen of 161 individuals developed fluid without symptoms. PWS over fluid areas at detection was reduced compared with 6 (difference −2.04 dB, P < 0.001) and 12 months (−2.27 dB, P < 0.001) prior. PWS over fluid areas was reduced compared with perifluid areas (difference −1.02 dB, P = 0.03), peripheral areas (−1.51 dB, P < 0.001), nonprogressed fellow eyes (−1.49 dB, P = 0.006), and nonprogressed age-matched intermediate AMD eyes (−2.29 dB, P = 0.001). No difference in BCVA was observed in eyes developing fluid compared to eyes that do not develop fluid (P = 0.76).ConclusionsRetinal areas with fluid on SD-OCT had a corresponding reduction in retinal sensitivity at the time of fluid detection compared with 6 and 12 months prior, in asymptomatic intermediate AMD without change in BCVA.Translational RelevanceDevelopment of self-monitoring tools to detect changes in retinal sensitivity may be helpful for early detection of retinal fluid suggestive of progression to neovascular AMD before acuity is affected.

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Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration

Cited by 18 publications

References 25 publications

Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration

Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration

Utility of the DHFR-based destabilizing domain across mouse models of retinal degeneration and aging

Presymptomatic Retinal Sensitivity Changes in Intermediate Age-Related Macular Degeneration Associated With New Retinal Fluid

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