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Michael DeNiro, Falah H. Al-Mohanna, Futwan Al-Mohanna; Targeting Zinc Transporter-8 as a Therapeutic Approach in Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5396.
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The Zinc (Zn) transporter encoded by SLC30A8, ZnT8, plays a particularly important role in Zn homeostasis in beta cells. Previous studies have indicated that an acute decrease in ZnT8 levels impairs beta cell function and Zn homeostasis and may contribute to the pathophysiology of diabetes. The link between ZNT8 and ischemic retinopathy has not been determined yet. It was the aim of this study to address the impact of ischemic retinopathy on the expression of ZnT-8 in vivo and in vitro.
We used an array of assays to evaluate the effects of YC-1, a small molecule inhibitor of HIF-1 and a novel NO-independent activator of soluble guanylyl cyclase (sGC) on ZNT8 expression; in vivo and in vitro.
We show that hypoxic/ischemic insult mediates a significant downregulation of ZnT8 at the message and the protein levels in the rat neurosensory cells (in vitro), and the ischemic retina (in vivo). Our data indicate that ZnT8-depleted cells are primarily localized in the neurosensory retina. Dual-injection regimen of YC-1 (100 μM) into the neovascular retinas, at post-natal day 12 (P12) and (P15) restores the ZnT8 levels to basal homeostatic level, which was comparable to those of the nontreated normoxic retinas.
Our data suggest that ischemic retinopathy maybe mediated by aberrant Zn homeostasis brought about by ZnT8 downregulation. In addition, YC-1 treatment plays a crucial role in impacting the ZnT8 expression level and Zn homeostasis.
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