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Peter Shaw, Hongjun Du, Diay Ho, Theodore Chin, Mike Matsumo, Adam May, Jingyao Chen, Xu Xiao; Oxidative stress impacts the AMD pathology through modulating Wnt signaling pathway. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5241.
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The canonical Wnt signaling plays a role in the pathogenesis of age-related macular degeneration (AMD). We hypothesize that insufficient systemic Wnt antagonist Dickkopf WNT signaling pathway inhibitor 1 (DKK1) would be associated with AMD status and oxidative stress would change the level of DKK1, and in turn impacts the AMD pathology. We tested the hypothesis by examining the plasma DKK1 level of diagnosed choroidal neovascular (CNV) patients and unaffected individuals. We also compared the DKK1 expression level of an experimental mouse model of oxygen-induced retinopathy (OIR) with untreated controls.
The peripheral blood of twenty-five CNV patients were obtained along with same sample size of unaffected individuals. We collected separate sets of peripheral blood from twenty-five individuals who currently smoke cigarettes and same sample size of individuals who never smoke. The plasma DKK1 level was measured by ELISA and analyzed using student t-test. We also performed the OIR on C57B/6 mice and untreated controls (n=8 in each group) and examined the expression of DKK1 gene in the retinas using quantitative PCR.
We have found that the plasma DKK1 level in control group (n=25) is significantly higher than CNV-affected group (n=25) (154348 ± 7322 vs. 126830 ± 4921, mean ± SEM measured by relative light units (RLU), p-value = 0.004). We also found that plasma DKK1 level in non-smoking group (n=25) is significantly higher than smoking group (n=25) (162737 ± 3772 vs. 139323 ± 5767, mean ± SEM measured by relative light units (RLU), p-value = 0.002). In addition, the expression of DKK1 gene in OIR treated mouse retinas is significantly lower than control untreated mouse retinas (n=8 in each group, 0.62 ± 0.15 vs. 1.06 ± 0.07, p=0.0025, measured DKK1 mRNA fold change after normalized with GAPDH).
We showed that plasma DKK1 level is decreased in the CNV patients in comparison to unaffected control subjects. Smoking, the major oxidative stress related environmental risk for AMD also decreases plasma DKK1. The oxidative stress responses in OIR model represses the expression of DKK1. These data indicate that oxidative stress may affect the expression of Wnt pathway inhibitors such as DKK1 resulting in less regulation of canonical Wnt signaling and leading to AMD pathogenesis and progression.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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