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Recent findings show that transformation of mild glomerulonephritis into end-stage disease coincides with shutdown of renal DNaseI expression in (NZBxNZW)F1 mice. Down-regulation of DNaseI results in reduced chromatin fragmentation and deposition of extracellular chromatin fragments in glomerular basement membranes where they appear in complex with IgG antibodies. Here, we implicate the anti-apoptotic and survival protein, tumor necrosis factor receptor-associated protein 1 (Trap1) in the disease process, based on the observation that annotated transcripts from this gene overlap with transcripts from the DNaseI gene. Furthermore, we translate these observations to human lupus nephritis. In this study, mouse and human DNaseI and Trap1 mRNA levels were determined by real-time quantitative PCR and compared with protein expression levels and clinical data. Cellular localization was analyzed by immune electron microscopy, IHC, and in situ hybridization. Data indicate that silencing of DNaseI gene expression correlates inversely with expression of the Trap1 gene. Our observations suggest that the mouse model is relevant for the aspects of disease progression in human lupus nephritis. Acquired silencing of the renal DNaseI gene has been shown to be important for progression of disease in both the murine and human forms of lupus nephritis. Early mesangial nephritis initiates a cascade of inflammatory signals that lead to up-regulation of Trap1 and a consequent down-regulation of renal DNaseI by transcriptional interference.

Original publication

DOI

10.1016/j.ajpath.2012.11.013

Type

Journal article

Journal

Am J Pathol

Publication Date

03/2013

Volume

182

Pages

688 - 700

Keywords

Adolescent, Adult, Animals, Biopsy, Deoxyribonuclease I, Disease Progression, Female, Gene Expression Regulation, HSP90 Heat-Shock Proteins, Humans, Immunoglobulin G, Immunohistochemistry, Intracellular Signaling Peptides and Proteins, Kidney, Lupus Nephritis, Male, Mice, RNA, Messenger, Young Adult