Abstract
ObjectiveTo define shared and unique features of SLE nephritis in mouse models of proliferative and glomerulosclerotic renal disease.MethodsPerfused kidneys from NZB/W F1, NZW/BXSB and NZM2410 mice were harvested before and after nephritis onset. Affymetrix based gene expression profiles of kidney RNA were analyzed using Genomatix Pathway Systems and Ingenuity Pathway Analysis software. Gene expression patterns were confirmed using real-time PCR.Results955, 1168 and 755 genes were regulated in the kidneys of nephritic NZB/W F1, NZM2410 and NZW/BXSB mice respectively. 263 genes were regulated concordantly in all three strains reflecting immune cell infiltration, endothelial cell activation, complement activation, cytokine signaling, tissue remodeling and hypoxia. STAT3 was the top associated transcription factor, having a binding site in the gene promoter of 60/263 regulated genes. The two strains with proliferative nephritis shared a macrophage/DC infiltration and activation signature. NZB/W and NZM2410 mice shared a mitochondrial dysfunction signature. Dominant T cell and plasma cell signatures in NZB/W mice reflected lymphoid aggregates; this was the only strain with regulatory T cell infiltrates. NZW/BXSB mice manifested tubular regeneration and NZM2410 mice had the most metabolic stress and manifested loss of nephrin, indicating podocyte loss.ConclusionsThese findings identify shared inflammatory mechanisms of SLE nephritis that can be therapeutically targeted. Nevertheless, the heterogeneity of effector mechanisms suggests that individualized therapy might need to be based on biopsy findings. Some common mechanisms are shared with non-immune–mediated renal diseases, suggesting that strategies to prevent tissue hypoxia and remodeling may be useful in SLE nephritis.
Highlights
Lupus nephritis is a devastating complication of SLE for which current treatment is insufficiently effective and excessively toxic
Principal component analysis of all genes expressed in the 3 strains showed a clear separation of the nephritic vs. non-nephritic mice as well as differences between strains (Figure 1C)
Other genes of interest include the TWEAK receptor FN14, whose expression on intrinsic renal cells promotes glomerulonephritis [17], ANKRD1, which is associated with proteinuria in SLE nephritis [18], TLRs 2 and 13, and several proteinase inhibitors of the Serpin family involved in the coagulation pathway
Summary
Lupus nephritis is a devastating complication of SLE for which current treatment is insufficiently effective and excessively toxic. It remains essential to study animal models [1] in which the whole organ can be studied without the confounding effects of medications In these studies, we used transcriptional profiling to define similarities and differences in the renal inflammatory process between three well-characterized models of SLE nephritis. Male NZW/BXSB mice carry the Yaa (Y linked autoimmune acceleration) locus containing a reduplication of the Tlr gene [4] They develop anti-RNA and anti-cardiolipin antibodies and proliferative glomerulonephritis with severe tubulointerstitial inflammation [5]. Differences in both pathogenic mechanisms and responses to immunologic interventions have been observed in the three models [6,7] These differences parallel the emerging appreciation of heterogeneity in human SLE nephritis [8,9]
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