Role of the Circadian Clock and Effect of Time-Restricted Feeding in Adenine-Induced Chronic Kidney Disease

Yina Fang, Sang Kyung Jo, Soo Ji Park, Jihyun Yang, Yoon Sook Ko, Hee Young Lee, Se Won Oh, Won Yong Cho, Kyoungmi Kim, Gi Hoon Son, Myung Gyu Kim

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Most physiological functions exhibit circadian rhythmicity that is partly regulated by the molecular circadian clock. Herein, we investigated the relationship between the circadian clock and chronic kidney disease (CKD). The role of the clock gene in adenine-induced CKD and the mechanisms of interaction were investigated in mice in which Bmal1, the master regulator of the clock gene, was knocked out, and Bmal1 knockout (KO) tubule cells. We also determined whether the renoprotective effect of time-restricted feeding (TRF), a dietary strategy to enhance circadian rhythm, is clock gene–dependent. The mice with CKD showed altered expression of the core clock genes with a loss of diurnal variations in renal functions and key tubular transporter gene expression. Bmal1 KO mice developed more severe fibrosis, and transcriptome profiling followed by gene ontology analysis suggested that genes associated with the cell cycle, inflammation, and fatty acid oxidation pathways were significantly affected in the mutant mice. Tubule-specific deletion of BMAL1 in HK-2 cells by CRISPR/Cas9 led to upregulation of p21 and tumor necrosis α and exacerbated epithelial-mesenchymal transition–related gene expression upon transforming growth factor β stimulation. Finally, TRF in the mice with CKD partially restored the disrupted oscillation of the kidney clock genes, accompanied by improved cell cycle arrest and inflammation, leading to decreased fibrosis. However, the renoprotective effect of TRF was abolished in Bmal1 KO mice, suggesting that TRF is partially dependent on the clock gene. Our data demonstrate that the molecular clock system plays an important role in CKD via cell cycle regulation and inflammation. Understanding the role of the circadian clock in kidney diseases can be a new research field for developing novel therapeutic targets.

Original languageEnglish
Article number100008
JournalLaboratory Investigation
Volume103
Issue number1
DOIs
Publication statusPublished - 2023 Jan

Bibliographical note

Publisher Copyright:
© 2022

Keywords

  • cell cycle
  • chronic kidney disease
  • circadian rhythm
  • inflammation
  • timed-restricted feeding

ASJC Scopus subject areas

  • General Medicine

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