Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli
Karin S. Peterson, … , Michael R. Jackson, Robert J. Winchester
Karin S. Peterson, … , Michael R. Jackson, Robert J. Winchester
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1722-1733. https://doi.org/10.1172/JCI19139.
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Article Autoimmunity

Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli

Abstract

The molecular pathogenesis of focal/diffuse proliferative lupus glomerulonephritis was studied by cDNA microarray analysis of gene expression in glomeruli from clinical biopsies. Transcriptional phenotyping of glomeruli isolated by laser-capture microscopy revealed considerable kidney-to-kidney heterogeneity in increased transcript expression, resulting in four main gene clusters that identified the presence of B cells, several myelomonocytic lineages, fibroblast and epithelial cell proliferation, matrix alterations, and expression of type I IFN–inducible genes. Glomerulus-to-glomerulus variation within a kidney was less marked. The myeloid lineage transcripts, characteristic of those found in isolated activated macrophages and myeloid dendritic cells, were widely distributed in all biopsy samples. One major subgroup of the samples expressed fibrosis-related genes that correlated with pathological evidence of glomerulosclerosis; however, decreased expression of TGF-β1 argued against its role in lupus renal fibrosis. Expression of type I IFN–inducible transcripts by a second subset of samples was associated with reduced expression of fibrosis-related genes and milder pathological features. This pattern of gene expression resembled that exhibited by activated NK cells. A large gene cluster with decreased expression found in all samples included ion channels and transcription factors, indicating a loss-of-function response to the glomerular injury.

Authors

Karin S. Peterson, Jing-Feng Huang, Jessica Zhu, Vivette D’Agati, Xuejun Liu, Nancy Miller, Mark G. Erlander, Michael R. Jackson, Robert J. Winchester

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Gene expression profiles of lupus glomeruli. (A and ...
Gene expression profiles of lupus glomeruli. (A and B) Hierarchical clustering analysis of 25 lupus glomeruli, isolated from 12 different SLE biopsies, and 6 control glomeruli, isolated from 4 different control kidneys. Each row corresponds to a cDNA on the microarray and each column, to a glomerular sample. Along the tops of A and B, each lupus sample is identified by a number in which the part before the dash identifies the biopsy and the part after the dash identifies the individual glomerular sample. In A, controls (*C) are shown and are identified by number as described above. The linear intensity scale ranges from fourfold or higher (+4) to minus fourfold or lower (_4). A positive “fold change” (yellow to red) indicates increased expression and a negative “fold change” (light to dark blue) indicates decreased expression in a glomerular sample compared with the average of the controls. A shows hierarchical clustering of 88 genes with increased expression and 89 genes with decreased expression in lupus glomeruli compared with the average of the controls, analyzed independently in sample set B12 and sample set B13. The location of some cDNA rows is indicated by their respective gene symbol along the right side of the clustering diagram. Supplemental Table 1 lists all genes that were clustered in A. B shows the combined hierarchical clustering of all genes with increased expression in lupus glomeruli in sample set B12 and B13. Four main gene clusters are shown (left margin) and are labeled as described in Results.