TY - JOUR
T1 - The glomerular circadian clock temporally regulates basement membrane dynamics and the podocyte glucocorticoid response
AU - Preston, Rebecca
AU - Chrisp, Ruby
AU - Dudek, Michal
AU - Paiva Teixeira Morais, Mychel
AU - Tian, Pinyuan
AU - Williams, Emily
AU - Naylor, Richard
AU - Davenport, Bernard
AU - Pathiranage, Dharshika
AU - Benson, Emma
AU - Spiller, David
AU - Bagnall, James
AU - Zeef, Leo
AU - Lawless, Craig
AU - Baker, Syed Murtuza
AU - Meng, Qing-Jun
AU - Lennon, Rachel
PY - 2025/1
Y1 - 2025/1
N2 - 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.
AB - 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.
U2 - 10.1016/j.kint.2024.10.016
DO - 10.1016/j.kint.2024.10.016
M3 - Article
SN - 0085-2538
VL - 107
SP - 99
EP - 115
JO - Kidney International
JF - Kidney International
IS - 1
ER -