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Stanniocalcin-1 is a Modifier of Oxygen-Induced Retinopathy Severity

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posted on 2019-08-28, 13:56 authored by Lauren A. Dalvin, Mary Elizabeth Hartnett, Colin A. Bretz, Cheryl R. Hann, Ricky Z Cui, Alan D. Marmorstein, David Sheikh-Hamad, Michael P. Fautsch, Gavin W. Roddy

Abnormal activation of signaling pathways related to angiogenesis, inflammation, and oxidative stress has been implicated in the pathophysiology of retinopathy of prematurity (ROP), a leading cause of blindness in pre-term infants. Therapies for ROP include laser and anti-vascular endothelial growth factor agents. However, these therapies have side effects, and even with adequate treatment, visual acuity can be impaired. Novel therapeutic options are needed. Stanniocalcin-1 (STC-1) is a neuroprotective protein with anti-inflammatory and anti-oxidative stress properties. Rodent models of oxygen-induced retinopathy (OIR) were selected to determine whether STC-1 plays a role in the development of OIR.

STC-1 gene and protein expression was first evaluated in the Sprague Dawley rat OIR model that is most similar to human ROP. OIR was then induced in wild-type and Stc-1−/- mice. Retinas were isolated and evaluated for avascular and neovascular area on retinal flat mounts. Quantification of gene expression by quantitative real-time PCR was performed. VEGF was assayed by ELISA in media obtained from induced pluripotent stem-cell-derived retinal pigment epithelial (iPS-RPE) cells following treatment with recombinant STC-1.

STC-1 was significantly upregulated in a rat model of OIR compared to room air controls at the gene (P < .05) and protein (P < .001) level. Stc-1−/- OIR mice showed significantly worse ROP compared to wild-type mice as assessed by avascular (20.2 ± 2.4% vs 15.2 ± 2.5%; P = .02) and neovascular area (14.3 ± 2.7% vs 8.8 ± 3.7%; P < .05). Transcript levels of vascular endothelial growth factor-A were significantly higher in Stc-1−/- OIR mice compared to wild-type controls (P = .03). STC-1 reduced VEGF production in iPS-RPE cells (P = .01).

STC-1 plays a role in the OIR stress response and development of pathologic vascular features in rodent OIR models by regulating VEGF levels.

Funding

Supported by Mayo Foundation (LAD, GWR); Veterans Affairs Merit Award BX002006 (DSH); EY21727 and EY26490 (MPF); R01 EY015130, R01 EY017011, T35EY026511, and R13EY029900, an Unrestricted Grant from Research to Prevent Blindness (to the Department of Ophthalmology & Visual Sciences, University of Utah), National Eye Institute Vision Core grant [EY014800] (MEH).

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