Progressive lupus nephritis : biological consequences of renal DNaseI gene silencing

Abstract

Systemic lupus erythematous (SLE) is an autoimmune syndrome which occurs most often between the ages 10-50 years. Lupus nephritis is the most severe clinical manifestation of SLE. 30-60% of the SLE patients may develop lupus nephritis during lifetime. At a certain time point in the life of (NZBxNZW) F1 mice prone to develop lupus nephritis, the expression of renal DNaseI endonuclease is lost. This result in accumulation of chromatin in glomeruli that are targeted by anti-chromatin antibodies results in development severe lupus nephritis. Understanding the mechanism(s) behind the renal DNaseI shut-down will be useful for future therapeutic targets to treat and prevent lupus nephritis. Our findings in this study revealed, however, a new direction to analyze the regulation of the DNaseI gene through transcriptional interference with the anti-apoptotic Trap 1 gene, possibly due to actions of pro-inflammatory cytokines. In the present study, we analyzed the biological consequence of renal DNaseI shut-down. Reduced chromatin fragmentation and exposure of chromatin in situ lead to, activation of toll like receptors (TLR) and Clec4e signaling pathways. Signaling molecules representing responses to activation of these receptors are shown to have a direct role on activation of the innate and adaptive immune system. Thus one central effect of these processes may be activation of chromatin-specific T and B cells, and a consequent production of antibodies reactive with components of chromatin. Activation of Clec4e in the context of lupus nephritis is a promising observation due to its link to secretion of MMPs, but also since this receptor has been shown to play a role in pathogenesis of glomerulonephritis. In the end, the observations presented in this study open for new possible pathways to describe lupus nephritis, and to identify new regulatory mechanisms for renal DNaseI. These processes must be further studied in detail, to analyse if they may provide insight into new possible therapies of lupus nephritis.