A Human Glomerular Transcriptional Profile of Endocapillary Proliferation Based on the Oxford Classification of IgA Nephropathy
Jeffrey B Hodgin, Celine Berthier, Rohan John, Elisabeth Grone, Stefan Porubsky, Hermann-Josef Grone, Matthias Kretzler, Heather Reich. University of Michigan, Ann Arbor, MI; German Cancer Research Centre, Heidelberg, Germany; University of Toronto, Toronto, Canada
Background: Our ability to identify patients at risk of progression in IgA nephropathy is inadequate and our understanding of the heterogeneous mechanisms responsible for loss of kidney function in this disease is limited. Recently, the Oxford classification of IgA nephropathy identified the presence of endocapillary proliferation as an independent predictor of renal-function decline. Our goal is to elucidate molecular mechanisms contributing to the development of endocapillary proliferation and subsequent loss of renal function.
Design: We analyzed human glomerular mRNA expression profiles obtained from microdissected kidney biopsies from an international cohort of 22 patients with IgA nephropathy. Biopsies were scored independently using the Oxford classification by three pathologists and a consensus score was generated. A list of differentially regulated genes (q<0.05) was generated for further analysis by comparing biopsies with endocapillary proliferation (E1; n=7) versus those without (E0; n=15).
Results: The E1 vs E0 comparison yielded 186 differentially expressed genes highly enriched for a macrophage expression signature. Gene ontology analysis revealed overrepresentation of biological processes related to proliferation and the cell cycle. Overrepresented canonical pathways included the E2F transcription factor network, and the FOXM1 transcription factor network, both of which play key roles in cell cycle progression. Furthermore, upregulation of multiple genes, including FOXM1, were significantly correlated with GFR. Foxm1 may be a therapeutic target for inhibition because it appears to be required for macrophage recruitment. Additional possible targets for therapeutic intervention in our dataset include the chemokine receptor CCR1 and the integrin ITGAM. Finally, we detect injury induced gene expression likely in mesangial cells (C5aR1, TNFAIP8) and endothelial cells (OSR1).
Conclusions: Defining the molecular pathways activated in the IgAN subgroup with endocapillary proliferation gives insight into mechanism of this progressive lesion. Macrophages have been described as key players in IgAN, but no study has yet analyzed an intraglomerular macrophage transcriptomic signature. This approach will allow further elucidation of important pathogenic pathways in IgAN progression, and may reveal new therapeutic targets for further analysis.
Category: Kidney (does not include tumors)
Tuesday, March 20, 2012 8:30 AM
Platform Session: Section H, Tuesday Morning