Multiomics reveals multilevel control of renal and systemic metabolism by the renal tubular circadian clock
Yohan Bignon, … , Frédéric Gachon, Dmitri Firsov
Yohan Bignon, … , Frédéric Gachon, Dmitri Firsov
Published March 2, 2023
Citation Information: J Clin Invest. 2023;133(8):e167133. https://doi.org/10.1172/JCI167133.
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Research Article Nephrology

Multiomics reveals multilevel control of renal and systemic metabolism by the renal tubular circadian clock

Abstract

Circadian rhythmicity in renal function suggests rhythmic adaptations in renal metabolism. To decipher the role of the circadian clock in renal metabolism, we studied diurnal changes in renal metabolic pathways using integrated transcriptomic, proteomic, and metabolomic analysis performed on control mice and mice with an inducible deletion of the circadian clock regulator Bmal1 in the renal tubule (cKOt). With this unique resource, we demonstrated that approximately 30% of RNAs, approximately 20% of proteins, and approximately 20% of metabolites are rhythmic in the kidneys of control mice. Several key metabolic pathways, including NAD+ biosynthesis, fatty acid transport, carnitine shuttle, and β-oxidation, displayed impairments in kidneys of cKOt mice, resulting in perturbed mitochondrial activity. Carnitine reabsorption from primary urine was one of the most affected processes with an approximately 50% reduction in plasma carnitine levels and a parallel systemic decrease in tissue carnitine content. This suggests that the circadian clock in the renal tubule controls both kidney and systemic physiology.

Authors

Yohan Bignon, Leonore Wigger, Camille Ansermet, Benjamin D. Weger, Sylviane Lagarrigue, Gabriel Centeno, Fanny Durussel, Lou Götz, Mark Ibberson, Sylvain Pradervand, Manfredo Quadroni, Meltem Weger, Francesca Amati, Frédéric Gachon, Dmitri Firsov

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Figure 7

Mitochondrial activity in Ctrl and cKOt mice.

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Mitochondrial activity in Ctrl and cKOt mice. (A–C) Oxygen consumption r...
(A–C) Oxygen consumption rates (OCR) of mitochondrial respiratory chain complexes I (CI), II (CII) or IV (CIV) in the kidneys of Ctrl and cKOt mice at ZT4 and ZT16. In A, data are presented as individual values, with mean ± SEM determined by 2-way ANOVA and Sidak’s multiple comparison posthoc tests. In B and C, data are resented as mean ± SEM and vertical dashed lines depict time-points of metabolic substrates injection during OCR measurement. (D) Heatmaps showing the relative expression and the fold change in mean expression of proteins forming CI to CIV complexes in the kidneys of Ctrl and cKOt mice. Statistics determined by limma comparison at 6 circadian time-points. Fold changes ≥ 1.10 are depicted in blue or red. Rhythmicity models are shown to the right of the heatmap. (E) Schematic of the Tricarboxylic acid (TCA) cycle and electron transport chain in mitochondrial matrix. Numbers are related to plots in H. (F and G) Plots showing the relative abundance of major TCA cycle metabolites at 6 circadian time points (F) or at ZT16 (G) in kidneys of Ctrl and cKOt mice. Data are individual values with mean ± SEM. In F, means were compared using limma and Padj < 0.1 are shown. In G, means were compared using 2-tailed multiple t tests and resulting P values were corrected using the FDR approach (2-stage Step-up method of Benjamini, Krieger and Yekutieli). (H) Temporal plots of fumarate and malate abundance with corresponding rhythmicity model and Padj from dryR and limma comparisons in kidneys of Ctrl and cKOt mice. SDH, Succinate dehydrogenase. *P < 0.05; **P < 0.001; ***P < 0.0001.