TY - JOUR
T1 - Transcription factor Ets-1 is essential for mesangial matrix remodeling
AU - Mizui, M.
AU - Isaka, Y.
AU - Takabatake, Y.
AU - Sato, Y.
AU - Kawachi, H.
AU - Shimizu, F.
AU - Takahara, S.
AU - Ito, T.
AU - Imai, E.
PY - 2006/7/7
Y1 - 2006/7/7
N2 - Most advanced glomerular diseases are characterized by abnormal extracellular matrix (ECM) accumulation in the glomeruli, and matrix metalloproteinases (MMPs) play a pivotal role in ECM remodeling in various glomerular diseases. The proto-oncogene, ets-1, is a transcription factor regulating the expression of various matrix proteinases, including MMP-1, MMP-3, and MMP-9. The goal of the present study was to characterize the role of Ets-1 in the progression of glomerular diseases. Overexpression of Ets-1 in cultured mesangial cells prevented transforming growth factor (TGF)-β-induced inhibition of DNA-binding activity and TGF-β-induced type I collagen production. In addition, exogenous Ets-1 abolished TGF-β-induced collagen gel contraction. The in vivo transfection of the ets-1 gene into nephritic kidney resulted in the increases in glomerular MMP-1, MMP-3, and MMP-9 mRNA, decreases in mesangial ECM deposition, and attenuation of fibronectin extradomain A (EDA) and type I collagen expression. In contrast, knockdown of Ets-1 in glomeruli resulted in severe ECM deposition in diseased glomeruli. In conclusion, Ets-1 promotes degradation of ECM proteins and is critical for integral glomerular reorganization.
AB - Most advanced glomerular diseases are characterized by abnormal extracellular matrix (ECM) accumulation in the glomeruli, and matrix metalloproteinases (MMPs) play a pivotal role in ECM remodeling in various glomerular diseases. The proto-oncogene, ets-1, is a transcription factor regulating the expression of various matrix proteinases, including MMP-1, MMP-3, and MMP-9. The goal of the present study was to characterize the role of Ets-1 in the progression of glomerular diseases. Overexpression of Ets-1 in cultured mesangial cells prevented transforming growth factor (TGF)-β-induced inhibition of DNA-binding activity and TGF-β-induced type I collagen production. In addition, exogenous Ets-1 abolished TGF-β-induced collagen gel contraction. The in vivo transfection of the ets-1 gene into nephritic kidney resulted in the increases in glomerular MMP-1, MMP-3, and MMP-9 mRNA, decreases in mesangial ECM deposition, and attenuation of fibronectin extradomain A (EDA) and type I collagen expression. In contrast, knockdown of Ets-1 in glomeruli resulted in severe ECM deposition in diseased glomeruli. In conclusion, Ets-1 promotes degradation of ECM proteins and is critical for integral glomerular reorganization.
KW - Gene therapy
KW - Mesangial cells
KW - TGF-β
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UR - http://www.scopus.com/inward/citedby.url?scp=33746126114&partnerID=8YFLogxK
U2 - 10.1038/sj.ki.5001541
DO - 10.1038/sj.ki.5001541
M3 - Article
C2 - 16738537
AN - SCOPUS:33746126114
SN - 0085-2538
VL - 70
SP - 298
EP - 305
JO - Kidney International
JF - Kidney International
IS - 2
ER -