Gene expression profiling of anti-GBM glomerulonephritis model: the role of NF-kappaB in immune complex kidney disease.
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-glomerular basement membrane (GBM) glomerulonephritis in mice using oligonucleotide microarray technology.


METHODS
Kidneys were harvested at days 1, 3, 7, 11, and 16 after inducing glomerulonephritis by using anti-GBM antibody. In parallel with examining the biochemical and histologic changes, gene expression profiles were acquired against five pooled control kidneys. Gene expression levels were cross-validated by either reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, or immunohistochemistry.


RESULTS
Pathologic changes in anti-GBM glomerulonephritis were confirmed in both BALB/c and C57BL/6 strains. Among the 13,680 spotted 65mer oligonucleotides, 1112 genes showing significant temporal patterns by permutation analysis of variance (ANOVA) with multiple testing correction [false discovery ratio (FDR) < 0.05] were chosen for cluster analysis. From the expression profile, acute inflammatory reactions characterized by the elevation of various cytokines, including interleukin (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 (ECM) genes. Although cytokines related to lymphocyte activation were not detected, monocyte or mesangial cell proliferation-related genes were increased. Tumor necrosis factor-alpha (TNF-alpha) and nuclear factor-kappaB (NF-kappaB) 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 time table for mouse anti-GBM glomerulonephritis model, providing a comprehensive overview on the mechanism governing the initiation and the progression of inflammatory renal disease.
Kim
Ju Han
JH
Seoul National University Biomedical Informatics (SNUBI), Seoul, Korea.
Ha
Il Soo
IS
Hwang
Chang-Il
CI
Lee
Young-Ju
YJ
Kim
Jihoon
J
Yang
Seung-Hee
SH
Kim
Yon Su
YS
Cao
Yun Anna
YA
Choi
Sangdun
S
Park
Woong-Yang
WY
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011817:Rabbits
D000936:Antigen-Antibody Complex; D016207:Cytokines; D016328:NF-kappa B