These lupus nephritis genes were further shown to not be associated with the normal ageing process based on the observed differences between healthy young and old C57BL6 mice. A broad range of biological functions was represented among the lupus nephritis genes identified in this study. As expected, given the loss of kidney function, the vast majority of genes involved in metabolic pathways are down regulated in nephritis and, given the inflammatory nature of the disease, many of the signalling pathway genes are up regulated. Glomerular disease is a sig nificant component in lupus nephritis. A recent study identified a glomerulus enriched gene set. We used data from this study to determine if the nephritis associated genes are enriched in the glomerular gene set.
We found a highly signif icant over representation of the glomerular genes consistent with glomerular involvement. A recent study by Liu and colleagues reported on 126 nephri tis associated genes in the MRLlpr model. Of these, 37 genes were present in the nephritis signature reported here. Commonalities were noted in the nephritis signatures between these two models, selleck chemicals such as the antigen presentation and complement pathways as well as various IFN regulated genes and immunoglobulins. A good overlap was also noted between our mouse nephritis gene set and 68 human lupus nephritis genes derived from laser captured glomeruli from SLE patients. Additional similarities may be present, but probably lie outside the statistical parameters of both datasets.
A profound normalisation of expression levels of lupus nephri tis genes was observed in mice treated with sirolimus, both for metabolic as well as signalling pathways. Affected metabolic pathways in lupus nephritis include fatty great post to read acid degradation, gly colysis pathways and leucinevalineisoleucine degradation. Transcripts for BCKDHA and DBT, two enzymes in the branched chain amino acid metabolism pathway required for the catabolism of leucine, valine and isoleucine, are reduced in nephritis, perhaps leading to the accumulation of leucine in diseased tissue. Interestingly, leucine activates the target of sirolimus inhibition, mTOR, leading to increased protein syn thesis, and in addition we noted an increase in ribosomal RNA transcripts in the disease state. This physiological con nection suggests that mTOR pathway activation may be increased by leucine in disease, providing perhaps an addi tional mechanism for sirolimus efficacy. Levels of these tran scripts were returned to asymptomatic levels in sirolimus treated mice. Several genes in the mitochondrial electron transport chain are also down regulated in the disease state, and mitochondrial dysfunction has been implicated in kidney function impairment.