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Inhibition of TGFBIp expression by lithium: implications for TGFBI-linked corneal dystrophy therapy

Title
 Inhibition of TGFBIp expression by lithium: implications for TGFBI-linked corneal dystrophy therapy 
Authors
 Seung-Il Choi ; Bong-Yoon Kim ; Eung Kweon Kim ; Tae-im Kim ; Hyunmi Ryu ; James V. Jester ; Shorafidinkhuja Dadakhujaev 
Issue Date
2011
Journal Title
 Investigative Ophthalmology & Visual Science 
ISSN
 0146-0404 
Citation
 Investigative Ophthalmology & Visual Science, Vol.52(6) : 3293~3300, 2011 
Abstract
PURPOSE. The purpose of this study was to investigate the effects and molecular mechanisms of lithium on inhibition of TGFBIp expression as a potential therapy for TGFBI-linked corneal dystrophy. METHODS. Primary culture corneal fibroblasts were isolated from the corneas of healthy subjects and patients with granular corneal dystrophy type 2 (GCD2) with a homozygous mutation in TGFBI R124H. Levels of TGFBIp and its mRNA in corneal fibroblasts treated with various lithium (LiCl) concentrations were analyzed by Western blot, RT-PCR, and quantitative real-time PCR. RESULTS. LiCl treatment reduced the expression levels of normal and mutant TGFBIp in a dose- and a time-dependent manner. Furthermore, TGF-β1-induced TGFBIp expression decreased by 35% and 67% after treatment with 5 mM and 10 mM LiCl, respectively. LiCl decreased the level of pSmad3 (S423/425) in a dose-dependent manner. Furthermore, LiCl increased the level of pGSK-3α/β (S21/9) in a dose-dependent manner. Also observed was the interaction between GSK-3β and Smad3, which was enhanced by lithium. In addition, Western blot analysis showed that the ratio of LC3-II/LC3-I in corneal fibroblasts increased after LiCl treatment. Cell viability at different doses was greater than 98%, indicating that LiCl did not induce significant corneal fibroblast death. Finally, the observed attenuating effects of LiCl on TGFBIp expression were not the results of cell death. CONCLUSIONS. The accumulation of mutant TGFBIp ultimately leads to the histopathologic and clinical manifestations associated with TGFBI-linked corneal dystrophy. These data strongly suggest that lithium may be used for the prevention or treatment of this disease.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/93253
DOI
10.1167/iovs.10-6405
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Ophthalmology
1. 연구논문 > 5. Research Institutes > Corneal Dystrophy Research Institute
1. 연구논문 > 1. College of Medicine > Yonsei Biomedical Research Center
Yonsei Authors
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