J Clin Invest.: co-auth.: GTF & PAF

J Clin Invest. 2023 Mar 2;e167133. doi: 10.1172/JCI167133. Online ahead of print.

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

Yohan Bignon 1Leonore Wigger 1Camille Ansermet 1Benjamin D Weger 2Sylviane Lagarrigue 1Gabriel Centeno 1Fanny Durussel 1Lou Götz 3Mark Ibberson 3Sylvain Pradervand 4Manfredo Quadroni 5Meltem Weger 2Francesca Amati 1Frédéric Gachon 2Dmitri Firsov 1


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

Keywords: Bioenergetics; Bioinformatics; Fatty acid oxidation; Nephrology.