expression profiling of anti-GBM glomerulonephritis model: the role of NFリB in
immune complex–mediated kidney disease
Kim1」, and Il Soo Ha2」, Chang-Il Hwang3,
Young-Ju Lee3, Jihoon Kim1, Seung-Hee Yang4,
Yon Su Kim4, Yun Anna Cao5, Sangdun Choi5,
National University Biomedical Informatics (SNUBI), 2Departments of
Pediatrics, 3Biochemistry and Molecular Biology, and 4Internal
Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea, 5Division
of Biology, California Institute of Technology, Pasadena, CA 91125, USA
Background. Immune complexes may cause an
irreversible onset of chronic renal disease. Most patients with chronic renal
disease undergo a final common pathway, marked by glomerulosclerosis and
interstitial fibrosis. We attempted to draw a molecular map of anti-GBM
glomerulonephritis (GN) in mice using oligonucleotide microarray technology.
Methods. Kidneys were harvested at days 1, 3, 7, 11 and 16 after inducing GN by using anti-GBM antibody. In parallel with examining the biochemical and histological changes, gene expression profile was acquired against five pooled control kidneys. Gene expression levels were cross-validated by either RT-PCR or immunohistochemistry.
Results. Pathological changes in anti-GBM GN were confirmed in both BALB/c and C57BL/6 strains. Among the 13,680 spotted 65mer oligonucleotides, 1,112 (FDR < 0.05) genes showing significant temporal patterns by permutation ANOVA with multiple-testing correction were chosen for cluster analysis. From the expression profile, acute inflammatory reactions characterized by the elevation of various cytokines, including IL-1 and IL-6, were identified within 3 days of disease onset. After 7 days, tissue remodeling response was prominent with highly induced extracellular-matrix genes. Although cytokines related to lymphocyte activation were not detected, monocyte or mesangial cell proliferation-related genes were increased. TNF-メ and NFリB pathway were consistently activated along the entire disease progression, inducing various target genes like complement 3, IL-1b, IL-6, Traf1 and Saa1.
Conclusions. We made a large-scale gene expression timetable for mouse anti-GBM GN model, providing a comprehensive overview on the mechanism governing the initiation and the progression of inflammatory renal disease.
See the 50 clusters for the significant 1,112 gene.
Biological Pathway Analysis
We conducted biological interpretation analysis of the 50 clusters.
The biological pathway analysis was conducted using ArrayXPath (accepted and will appear in Nucleic Acids Research, 2004 July), a recently developed bioinformatics tool by SNUBI.
microarray data illustrated in this paper were submitted to the Gene Expression
Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession numbers
GSM15078-GSM15092, GSE954-GSE958, and GSE969.
Supplementary quality plot for the statistical significance analysis using permutation ANOVA.
GO Annotations for the 50 clusters.>