Renal expression of the Ets-1 proto-oncogene during progression of rat crescentic glomerulonephritis.
The ets-1 proto-oncogene is a member of the transcriptional factor family and was identified by homology to the v-ets oncogene. It was recently demonstrated that Ets-1 protein interacts with the promoter region of the genes coding for proteinases, including matrix metalloproteinase-1 (MMP-1), MMP-3, and urokinase-type plasminogen activator, suggesting that it may play an important role in the regulation of MMP expression. The role of the ets-1 proto-oncogene in advanced glomerular diseases, where extracellular matrix accumulation is observed, remains undefined. In this study, the expression of ets-1 mRNA and protein during the progression of rat crescentic glomerulonephritis was examined using immunohistochemical analysis, reverse transcription-PCR, and in situ hybridization. Passive accelerated anti-glomerular basement membrane-induced nephritis was induced in rats by intravenous injection of nephrotoxic serum. Rats were euthanized on day 7, 14, 21, 28, or 42. Immunohistochemical analysis demonstrated significant upregulation of Ets-1 protein expression in glomeruli and the interstitium in anti-glomerular basement membrane-induced nephritis. The numbers of Ets-1-positive cells were increased 8.8-fold on day 21 in glomeruli (1.2+/-0.1 cells/glomerular cross-section, P<0.001) and sixfold on day 28 in the interstitium (21+/-1.3 cells/mm(2), P<0.001), compared with control samples. Ets-1 protein was predominantly localized in glomerular epithelial cells, endothelial cells, and interstitial cells. A small number of vascular endothelial cells, macrophages, and T cells also expressed Ets-1 protein. MMP-3 deposition was upregulated and positive cells in the interstitium often coexpressed Ets-1, whereas only a few glomerular cells were positive for both MMP-3 and Ets-1 protein. The expression of ets-1 mRNA was also markedly increased in diseased kidneys. The distribution of ets-1 mRNA was similar to that of the protein. These results indicate that overexpression of the ets-1 proto-oncogene by phenotypically altered renal cells might be associated with the pathogenesis of rat crescentic glomerulonephritis.
Naito
Takashi
T
Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan.|Department of Medicine, Kidney Center, Tokyo Women's Medical College, Tokyo, Japan.
Razzaque
Mohammed S
MS
Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan.
Nazneen
Arifa
A
Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan.
Liu
Diange
D
Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan.
Nihei
Hiroshi
H
Department of Medicine, Kidney Center, Tokyo Women's Medical College, Tokyo, Japan.
Koji
Takehiko
T
Department of Histology and Cell Biology, Nagasaki University School of Medicine, Nagasaki, Japan.
Taguchi
Takashi
T
Second Department of Pathology, Nagasaki University School of Medicine, Nagasaki, Japan.
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000378:metabolism; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D005921:Glomerulonephritis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology / Q000652:urine; D007150:Immunohistochemistry / Q000379:methods; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D011507:Proteinuria / Q000652:urine; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
C494043:Ets1 protein, rat; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors; D019278:Matrix Metalloproteinase 3