Angiographic Features of Transgenic Mice With Increased Expression of Human Serine Protease HTRA1 in Retinal Pigment Epithelium

Kumar, Sunil; Berriochoa, Zachary; Ambati, Balamurali K.; Fu, Yingbin

doi:10.1167/iovs.13-13111

Cited by 27 publications

(27 citation statements)

References 38 publications

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“…We formulated new hypotheses testable in longitudinal imaging of patients receiving anti-VEGF therapy and in animal models with genetic predisposition to neovascularization. 63, 64 Importantly our data support three anatomical markers of potential utility in assessing via SDOCT and FAF whether RPE death in nvAMD is due to an underlying degeneration or secondary to exudation, with or without VEGF suppression. Relative to eyes with GA, eyes with nvAMD lack the progressive dysmorphia and thickening of the RPE layer toward the ELM descent, have thinner combined RPE+BLamD, and tend to have obliquely oriented, straight ELM descents.…”

Section: Discussionsupporting

confidence: 67%

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Atrophy in Neovascular Age-Related Macular Degeneration

Zanzottera

Ach

Huisingh

et al. 2016

Retina

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Purpose To enable future studies of retinal pigment epithelium (RPE) fate in the macular atrophy occurring in eyes with neovascular AMD (nvAMD), we determined how RPE morphology changes across the transition from health to atrophy in donor eyes with nvAMD. Method In RPE-Bruch’s membrane flat mounts of 5 nvAMD eyes the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histological sections of 27 nvAMD eyes, RPE phenotypes were assessed at ±500 and ±100 µm from the descent of the external limiting membrane (ELM) towards Bruch’s membrane. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE+BLamD were determined. Shapes of the ELM descent were recorded. Results Approaching the ELM descent, the percentage of different RPE phenotypes (Zanzottera, IOVS 2015) and the thickness of RPE, BLamD, and RPE + BLamD each stayed roughly constant. When compared to a separately described cohort of eyes with geographic atrophy, eyes with nvAMD were more likely to have RPE dysmorphia that did not worsen towards the atrophy border, thinner BLamD overall (3.25 ± 3.46 µm vs 7.99 ± 7.49 µm for geographic atrophy), and a higher proportion of oblique ELM descents (47.9% vs 31.9%). Conclusion The distribution of RPE phenotypes at the transition to macular atrophy in eyes with nvAMD differs from that in primary geographic atrophy, likely reflecting greater photoreceptor loss and the effects of exudation in nvAMD. This distribution, the shape of ELM descents, and thickness profiles may be useful metrics in clinical studies of macular atrophy utilizing optical coherence tomography and fundus autofluorescence.

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Section: Discussionsupporting

confidence: 67%

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Atrophy in Neovascular Age-Related Macular Degeneration

Zanzottera

Ach

Huisingh

et al. 2016

Retina

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“…One of these variants is located in the HtrA1 promoter region (rs11200638) ( Dewan et al, 2006 , Fritsche et al, 2016 , Yang et al, 2006 ) and has been strongly suggested to have a putative role in the AMD pathogenesis. In support of this notion, transgenic mice overexpressing HtrA1 in RPE cells recapitulated features associated with advanced AMD and polypoidal choroidal vasculopathy (PCV) such as: degradation of the Bruch's membrane, increased damage of the Bruch's membrane upon exposure to cigarette smoke, and increase of PCV lesions ( Iejima et al, 2015 , Jones et al, 2011 , Kumar et al, 2014 , Nakayama et al, 2014 , Vierkotten et al, 2011 ). HtrA1 is a member of the high-temperature requirement A family of the serine proteases and contains a homologous active domain to the bacterial serine protease which is responsible for the proteolytic activity ( Eigenbrot et al, 2012 ).…”

Section: Introductionmentioning

confidence: 82%

HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model

et al. 2018

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Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss. The protein HtrA1 is enriched in retinal pigment epithelial (RPE) cells isolated from AMD patients and in drusen deposits. However, it is poorly understood how increased levels of HtrA1 affect the physiological function of the RPE at the intracellular level. Here, we developed hfRPE (human fetal retinal pigment epithelial) cell culture model where cells fully differentiated into a polarized functional monolayer. In this model, we fine-tuned the cellular levels of HtrA1 by targeted overexpression. Our data show that HtrA1 enzymatic activity leads to intracellular degradation of tubulin with a corresponding reduction in the number of microtubules, and consequently to an altered mechanical cell phenotype. HtrA1 overexpression further leads to impaired apical processes and decreased phagocytosis, an essential function for photoreceptor survival. These cellular alterations correlate with the AMD phenotype and thus highlight HtrA1 as an intracellular target for therapeutic interventions towards AMD treatment.

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“…Specifically, the rs11200638 variant in the promoter region of HTRA1, which is identified as a major risk allele for AMD, results in elevated HTRA1 expression (DeWan et al, ). In addition, HTRA1 up‐regulation in RPE appears to result in RPE atrophy and photoreceptor degeneration as well as CNV (Jones et al, ; Kumar, Berriochoa, Ambati, & Fu, ; Melo et al, ). Although extrapolation of findings from in vitro studies suggests a potential reduction in the HTRA1 activity in the presence of the S‐163R‐CTRP5 in vivo, currently molecular assays to selectively measure HTRA1 activity in vivo in the L‐ORD mouse models have not been established.…”

Section: Discussionmentioning

confidence: 99%

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

et al. 2019

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Late‐onset retinal degeneration (L‐ORD) is an autosomal dominant macular degeneration characterized by the formation of sub‐retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L‐ORD results from mutations in the C1q‐tumor necrosis factor‐5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L‐ORD pathology, we used a human cDNA library yeast two‐hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM‐Ch) from wild‐type (Wt), heterozygous S163R Ctrp5 mutation knock‐in (Ctrp5S163R/wt), and homozygous knock‐in (Ctrp5S163R/S163R) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C‐terminal PDZ‐binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R‐CTRP5 protein also binds to HTRA1 but is resistant to HTRA1‐mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM‐Ch of Ctrp5S163R/S163R and Ctrp5S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L‐ORD pathology.

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Angiographic Features of Transgenic Mice With Increased Expression of Human Serine Protease HTRA1 in Retinal Pigment Epithelium

Abstract: Transgenic hHTRA1(+) mice exhibit a rich spectrum of "clinical" features that closely mimic human PCV. This animal model will serve as an invaluable tool for future mechanistic and translational studies of PCV and other forms of choroidal vasculopathies.

Cited by 27 publications

References 38 publications

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Atrophy in Neovascular Age-Related Macular Degeneration

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Atrophy in Neovascular Age-Related Macular Degeneration

HtrA1 Mediated Intracellular Effects on Tubulin Using a Polarized RPE Disease Model

Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

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