Transcription factor Ets-1 is essential for mesangial matrix remodeling.
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)-beta-induced inhibition of DNA-binding activity and TGF-beta-induced type I collagen production. In addition, exogenous Ets-1 abolished TGF-beta-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.
Mizui
M
M
Department of Nephrology, Osaka University Graduate School of Medicine (A8), Suita, Japan.
Isaka
Y
Y
Takabatake
Y
Y
Sato
Y
Y
Kawachi
H
H
Shimizu
F
F
Takahara
S
S
Ito
T
T
Imai
E
E
D000818:Animals; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D051381:Rats; D016212:Transforming Growth Factor beta / Q000378:metabolism
C494043:Ets1 protein, rat; D016326:Extracellular Matrix Proteins; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1