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B. Zhang, K. Zou, J.-X. Ma; SERPINA3K, an Extracellular SERPIN Member, Inhibits Fibrogenesis in Diabetic Retinopathy via Blocking the WNT/Beta-Catenin Pathway. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6170.
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© ARVO (1962-2015); The Authors (2016-present)
SERPINA3K belongs to the serine proteinase inhibitor family. We have shown previously that SERPINA3K levels are decreased in the retina of a diabetic animal model, which may contribute to diabetic retinopathy (DR). It has been suggested that fibrosis is a common pathological change in DR. One of the pro-fibrogenic factors, connective tissue growth factor (CTGF), has been found to be up-regulated in the retinas in DR. The purpose of this study is to investigate whether SERPINA3K inhibits retinal fibrosis induced by diabetes and elucidate the potential mechanism of action.
Retinal Müller cells and retinal pigment epithelial (RPE) cells were exposed to a medium with 30 mM glucose. Diabetes was induced in adult Brown Norway rats with an intraperitoneal injection of streptozotocin (STZ) and monitored with measuring blood glucose concentrations. SERPINA3K was delivered by an intravitreal injection of the adenovirus vector, 2 months after the onset of diabetes, and the retinas were collected 1 month following the intravitreal injection. The TOP-FLASH promoter assay system was used to measure the TCF/LEF promoter activity.
CTGF levels were significantly elevated in the retina of the diabetic rats and significantly reduced by SERPINA3K. SERPINA3K also decreased the expression of CTGF in the retinal cell culture in the high glucose medium. Further, SERPINA3K blocked the accumulation of beta-catenin, a down-stream effector in the canonical Wnt pathway, in the diabetic retinas and in the retinal cells exposed to high glucose. Moreover, SERPINA3K significantly decreased the high glucose-induced phosphorylation of low-density lipoprotein receptor-related protein 6 (LRP6), a co-receptor for the Wnt ligand. In cultured cells, high glucose sequentially induced the phosphorylation of LRP6, stabilization of beta-catenin and over-expression of CTGF. On the other hand, WNT3A, one of the WNT ligands, induced the WNT activity and CTGF over-expression in the cultured RPE cells, same as the high glucose treatment, indicating that CTGF is a WNT-regulated gene in the high glucose model. SERPINA3K attenuated the WNT3A-induced phosphorylation of LRP6, accumulation of beta-catenin, increase of the TCF promoter activity and the over-expression of CTGF. These results suggest that WNT signaling activation was an upstream event in DR and the anti-WNT activity of SERPINA3K is the potential mechanism responsible for its anti-fibrogenic functions.
SERPINA3K is an anti-fibrogenic factor and has therapeutic potential for DR. This function may be mediated by its inhibitory effect on the canonical WNT pathway.
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