Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: Our goal was to use transcriptome analysis to elucidate the molecular mechanisms involved in the immunopathogenesis of renal inflammation during the onset, remission and impending relapse of nephritis in the NZB/W murine lupus model.
Methods: Targeted microarray analysis was performed on perfused kidneys obtained from NZB/W F1 mice at intervals during their disease course or after remission induction by cyclophosphamide combined with six doses of CTLA4Ig and anti-CD154 or by a combination CTLA4Ig and TACI-Ig. Validation of the differentially expressed genes was performed using real time PCR analysis. Comparisons between groups using SAM, and unbiased analysis of the entire dataset using Kohonen Networks were performed.
Results: Few changes in the renal molecular profile were detected prior to the onset of proteinuria but a significant shift in gene expression occurred at proteinuria onset. This profile reflected dendritic cell/macrophage and lymphoid cell infiltration and complement activation. As disease progressed, subsequent changes in gene expression predominantly reflected mitochondrial dysfunction and metabolic stress. Remission induction resulted in reversal of much of the inflammatory gene expression pattern however there was incomplete reversal of genes associated with early renal fibrosis, endothelial injury and hypoxia. Progression towards relapse was associated with increasing mitochondrial dysfunction and metabolic stress that preceded the onset of proteinuria. Using an unbiased approach we identified a major pattern of gene expression that was associated with proteinuria onset, nephritis progression and relapse. The top biological process identified for these genes was mitochondrial dysfunction. Finally, using Kohonen Networks we identified two major patterns of gene expression associated with progressive disease. The first, that associated with proteinuria onset and reversed with remission, involved multiple inflammatory pathways whereas the second, that associated with nephritis progression and relapse, involved multiple metabolic pathways. Using qRT-PCR we examined informative genes in a second murine lupus model NZM2410, in which remission of nephritis was induced with BAFF inhibition. While progression towards relapse was associated with recruitment of pro-inflammatory genes, the expression pattern that distinguished kidneys of mice harvested >30 weeks after remission induction from kidneys of mice with proteinuria and renal damage indicated that renal hypoxia, endothelial cell activation, tissue remodeling and tubular damage were the major mediators of renal loss.
Conclusion: Our findings show that immune cell infiltration and activation is associated with proteinuria onset and reverses with immunosuppressive therapy but that disease progression and impending relapse is associated with increasing renal hypoxia and metabolic stress. These findings suggest that that as nephritis progresses or during nephritis flares, therapeutic targeting only of inflammation becomes less likely to prevent eventual renal decline. Optimal therapy of SLE nephritis should target both immune and non-immune disease mechanisms.
C. C. Berthier,
H. D. Li,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-stage-specific-genes-associated-with-lupus-nephritis-and-response-to-remission-induction-in-nzbw-mice/