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

Posted on by

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

Abstract

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.