The glomerular circadian clock temporally regulates basement membrane dynamics and the podocyte glucocorticoid response

Abstract

Kidney physiology shows diurnal variation, and a disrupted circadian rhythm is associated with kidney disease. However, it remains largely unknown whether glomeruli, the filtering units in the kidney, are under circadian control. Here, we investigated core circadian clock components in glomeruli, together with their rhythmic targets and modes of regulation. With clock gene reporter mice, cell-autonomous glomerular clocks which likely govern rhythmic fluctuations in glomerular physiology were identified. Using circadian time-series transcriptomic profiling, the first circadian glomerular transcriptome with 375 rhythmic transcripts, enriched for extracellular matrix and glucocorticoid receptor signaling ontologies, were identified. Subsets of rhythmic matrix-related genes required for basement membrane assembly and turnover, and circadian variation in matrix ultrastructure, coinciding with peak abundance of rhythmic basement membrane proteins, were uncovered. This provided multiomic evidence for interactions between glomerular matrix and intracellular time-keeping mechanisms. Furthermore, glucocorticoids, which are frequently used to treat glomerular disease, reset the podocyte clock and induce rhythmic expression of potential glomerular disease genes associated with nephrotic syndrome that included Nphs1 (nephrin) and Nphs2 (podocin). Disruption of the clock with pharmacological inhibition altered the expression of these disease genes, indicating an interplay between clock gene expression and key genes required for podocyte health. Thus, our results provide a strong basis for future investigations of the functional implications and therapeutic potential of chronotherapy in glomerular health and disease.

Keywords: basement membrane; circadian rhythm; glucocorticoids; podocytes.