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

 Seung-Il Choi  ;  Bong-Yoon Kim  ;  Eung Kweon Kim  ;  Tae-im Kim  ;  Hyunmi Ryu  ;  James V. Jester  ;  Shorafidinkhuja Dadakhujaev 
 Investigative Ophthalmology & Visual Science, Vol.52(6) : 3293-3300, 2011 
Journal Title
 Investigative Ophthalmology & Visual Science 
Issue Date
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.
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실)
1. Journal Papers (연구논문) > 5. Research Institutes (연구소) > Corneal Dystrophy Research Institute (각막이상증연구소)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원)
Yonsei Authors
김봉윤(Kim, Bong Yoon) ; 김응권(Kim, Eung Kweon) ; 김태임(Kim, Tae Im) ; 류현미(Ryu, Hyun Mi) ; 최승일(Choi, Seung Il)
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