Circadian Reprogramming of Protein Homeostasis and Glycolipid Metabolism in Diabetic Nephropathy

ABSTRACT Dysfunction of the circadian clock has been implicated in the pathogenesis of various diseases, including metabolic disorders, inflammatory conditions, and cancer. While the significance of circadian rhythm in diabetic nephropathy is gaining attention, the specific alterations in circadian profiles in diabetic nephropathy remain unexplored. In the present study, we performed RNA sequencing on renal cortex samples collected every 4 h across the day from both control and diabetic mice. The rhythmicity of genes was identified using the JTKCYCLE algorithm for each group. Genes that lost, acquired, or sustained rhythmicity in diabetic mice were denoted the circadian dysregulation gene set. Subsequent bioinformatic analyses focused on this gene set to investigate the circadian reprogramming in diabetic nephropathy. We observed significant circadian disruption in the kidney of diabetic mice, marked by both the gain and loss of rhythmicity, along with alterations in the phase and relative amplitude of genes that retained rhythmic expressions. Circadian disturbances, such as phase shifts and alterations in relative amplitude or mesor, were also noted in core clock genes. Furthermore, genes that lost rhythmicity in diabetic nephropathy were predominantly associated with protein homeostasis and glycolipid metabolism, whereas those that gained rhythmicity were mainly linked to gene regulation, fatty acid metabolism, and protein transport. The genes in the circadian dysregulation gene set that exhibit differential expression at least at one Zeitgeber time were most prominently enriched in the lipid metabolic process. WGCNA and correlation analysis revealed co‐expression networks involving core clock genes and PPAR signaling pathway with renal triglyceride levels. Our study reveals substantial circadian disruption in diabetic nephropathy, with significant impacts on protein homeostasis and glycolipid metabolism. Furthermore, our findings highlight the potential influence of circadian system dysregulation on the disorder of fatty acid metabolism in diabetic nephropathy.