Altered renal circadian rhythm in SLE nephritis

Circadian oscillation in expression of approximately 10% of the transcriptome synchronizes various behavioral, biochemical, and physiological processes, allowing all organisms to anticipate and respond to changes in their environment. Disruption of circadian rhythm has important consequences for human health. Control of circadian rhythm is dependent on a set of transcription factors that regulate each other through feed-forward loops. There is both a central pacemaker and a set of organ specific pacemakers. In the kidneys for example, GFR, renal blood flow, urine excretion and electrolyte excretion are all subject to daily oscillations. Furthermore circadian oscillations in the immune system affect responses to pathogens and inflammation.  We have recently found a disturbance of expression of key clock transcriptional regulators in the kidneys of mice with SLE nephritis. We hypothesize that dysfunction of the renal circadian clock contributes to the amplification of inflammatory circuits in lupus nephritis. Our goals are to confirm circadian dysfunction at protein level, to determine whether the dysfunction affects the renal parenchyma and/or infiltrating inflammatory cells and whether deficiency or overexpression of the master transcriptional regulator BMAL1 impacts on lupus severity. Our findings set the stage for testing therapies that target the molecular clock.