Cited 41 times in

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

Authors
 Seung-Il Choi  ;  Bong-Yoon Kim  ;  Shorafidinkhuja Dadakhujaev  ;  James V. Jester  ;  Hyunmi Ryu  ;  Tae-im Kim  ;  Eung Kweon Kim 
Citation
 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol.52(6) : 3293-3300, 2011 
Journal Title
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
ISSN
 0146-0404 
Issue Date
2011
MeSH
Autophagy/drug effects ; Blotting, Western ; Cells, Cultured ; Cornea/cytology ; Corneal Dystrophies, Hereditary/drug therapy* ; Corneal Dystrophies, Hereditary/pathology ; Dose-Response Relationship, Drug ; Extracellular Matrix Proteins/genetics* ; Extracellular Matrix Proteins/metabolism ; Fibroblasts/drug effects* ; Fibroblasts/metabolism ; Gene Expression Regulation/drug effects* ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Lithium Chloride/pharmacology* ; Phosphorylation ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Smad3 Protein/metabolism ; Time Factors ; Transforming Growth Factor beta/antagonists & inhibitors ; Transforming Growth Factor beta/genetics* ; Transforming Growth Factor beta/metabolism
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.
Files in This Item:
T201101444.pdf Download
DOI
10.1167/iovs.10-6405
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Bong Yoon(김봉윤)
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Kim, Tae-Im(김태임) ORCID logo https://orcid.org/0000-0001-6414-3842
Ryu, Hyun Mi(류현미)
Choi, Seung Il(최승일) ORCID logo https://orcid.org/0000-0001-7168-8795
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/93253
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links