Background/Purpose: Mouse models are useful for studying the pathogenesis of SLE nephritis but it is not clear which model is the most appropriate for understanding human disease. The goal of this study was to understand both shared and unique features of SLE nephritis in mouse models of proliferative and glomerulosclerotic renal disease

Methods: Perfused kidneys from NZB/W F1, NZW/BXSB and NZM2410 mice were harvested before and after nephritis onset. Affymetrix based expression profiles of whole kidney RNA were analyzed using Genomatix Pathway Systems and Ingenuity Pathway Analysis software. Fold-change ≥1.4 for the up-regulated genes and ≤ 0.7 for the down-regulated genes and q <0.001 were chosen as cut-off values. Only those genes with human orthologs were analyzed. Confirmation of gene expression patterns was performed using real-time PCR.

Results: 955, 1168 and 835 genes were regulated in the kidneys of nephritic NZB/W F1, NZW/BXSB and NZM2410 mice respectively. 263 genes were regulated in all three strains reflecting immune cell infiltration, endothelial cell activation, fibrinolysis, complement activation and cytokine signaling. STAT3 was the top transcription factor having a binding site in the regulated gene promoter and IL-6 signaling was a top pathway in the ingenuity analysis. Each strain also expressed a unique pattern of genes. NZB/W mice had dominant T cell and  IL-1 signatures whereas NZW/BXSB mice had prominent integrin, complement signatures and p53 signatures. NZM2410 mice that have severe glomerulosclerosis and scant lymphocytic infiltrates had a dominant metabolic and mitochondrial dysfunction signature; part of this signature was shared with NZB/W mice. The two strains with proliferative disease NZB/W and NZW/BXSB shared a macrophage/DC infiltration and activation signature. Importantly, overlapping signatures with human SLE biopsies were observed for all three mouse strains.

Using real-time PCR we confirmed these gene expression profiles and showed significant differences in the inflammatory response between strains. For example regulatory T cells infiltrated the kidneys of NZB/W mice but not the other two strains. NZM2410 mice had features of renal macrophage activation but lacked dendritic cell infiltration and had less endothelial cell activation than the other two strains. Loss of nephrin, indicating podocyte death, was most marked in the NZM2410 strain and was not observed in NZW/BXSB mice. Robust markers of interstitial disease/remodeling and hypoxia were shared between nephritic mice of all three strains. IL1F6, a marker of tubular dysfunction was an earlier marker of proteinuria than Lcn2.

Conclusion: These findings among genetically related strains of SLE prone mice illustrate the heterogeneity of renal responses to immune complex deposition and inflammation and suggest that individualized targeting of effector mechanisms might need to be based on biopsy findings. These findings further suggest that the progression of renal impairment in SLE shares many common mechanisms with other non-immune–mediated renal diseases and that strategies currently being applied in other diseases to prevent tissue hypoxia and remodeling may also be useful in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/shared-and-unique-molecular-features-of-nephritis-in-3-models-of-murine-sle/