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

Feb 7, 2023Laboratory investigation; a journal of technical methods and pathology

How the Body's Internal Clock and Limited Meal Times Relate to Kidney Disease Caused by Adenine

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Abstract

Mice with chronic kidney disease showed altered expression of core clock genes and loss of diurnal variations in renal functions.

Knockout of the Bmal1 gene in mice led to more severe kidney fibrosis.
Transcriptome profiling indicated significant impacts on genes related to cell cycle, inflammation, and fatty acid oxidation in Bmal1 knockout mice.
Deletion of BMAL1 in kidney cells increased the expression of p21 and tumor necrosis factor alpha, worsening the response to injury.
Time-restricted feeding partially restored the disrupted oscillation of kidney clock genes in mice with chronic kidney disease.
The protective effects of time-restricted feeding were diminished in Bmal1 knockout mice, indicating a partial dependence on the clock gene.

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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.

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

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