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 antivascular 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 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<0.05) and protein (P<0.001) 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=0.02) and neovascular area (14.3 ± 2.7% vs 8.8 ± 3.7%; P<0.05).

Stanniocalcin-1 (STC-1), a downstream effector molecule in latanoprost signaling, acts independent of the FP receptor for intraocular pressure reduction

“…In addition to calcium metabolism, STC-1 has been shown to be cytoprotective by regulating oxidative stress [38][39][40][41][42][43] and inflammation, [43][44][45][46] and be neuroprotective for cerebral neurons, retinal photoreceptors, and retinal ganglion cells [47][48][49][50]. More recently, we demonstrated that STC-1 also has a role in development of the oxygen induced retinopathy stress response [51]. Though recent work has shown that megalin can act as a shuttle protein to transport STC-1 to the mitochondria, a potential cellular receptor has…”

Oxidative Stress Markers and the Retinopathy of Prematurity

“…Another molecule that seems to have a defensive effect against oxidative stress is stanniocalcin-1 (STC-1), which is a neuroprotective protein with anti-inflammatory and antioxidative stress properties [56]. STC-1 plays a role in the OIR stress response and development of pathologic vascular features in rodent OIR models by regulating VEGF levels [56]. STC-1 is a multifunctional protein that is upregulated by cellular stresses [57][58][59][60].…”

“…The present data suggest STC-1 modulates OIR severity, in part, due to its effect on VEGF production. The reduction of avascular and neovascular retinas in the presence of STC-1 might be associated with neuroprotective and anti-VEGF effects [56,[63][64][65].…”

Characterization of stanniocalcin-1 expression in macrophage differentiation

“…Moreover, the counteracting effects of STC1 on LPS-induced lung injury [ 15 ] or ischemic cardiac injury in mice [ 16 ], via inhibition of inflammatory cascades or suppression on monocytes/macrophages recruitment were revealed respectively. The anti-inflammatory effects of STC1 on other models, like osteoarthritis [ 17 ], and retinopathy [ 18 ] were reported.…”