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

ABSTRACT

Purpose/Aim

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.

Materials and methods

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.

Results

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).

Conclusions

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

KEYWORDS:

• Retinopathy of prematurity
• oxygen induced retinopathy
• Stanniocalcin-1
• STC-1

Contributions of the authors

Lauren A. Dalvin, generation, and analysis of experimental data, editing of manuscript.

Mary Elizabeth Hartnett, planning of studies, generation and analysis of experimental data, editing of manuscript.

Colin A. Bretz, generation of experimental data, editing of manuscript.

Cheryl R. Hann, generation of experimental data.

Ricky Z. Cui, generation of experimental data.

Alan D. Marmorstein, planning of experiments.

David Sheikh-Hamad, provision of study materials, editing of manuscript.

Michael P. Fautsch, planning of studies, generation and analysis of experimental data, editing of manuscript.

Gavin W. Roddy, planning of studies, generation and analysis of experimental data, writing and editing of manuscript.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

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).