Nephron-Specific Deletion of Circadian Clock Gene Bmal1 Alters the Plasma and Renal Metabolome and Impairs Drug Disposition.

Détails

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Etat: Public
Version: Author's accepted manuscript
ID Serval
serval:BIB_36AAA7DF76DA
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Nephron-Specific Deletion of Circadian Clock Gene Bmal1 Alters the Plasma and Renal Metabolome and Impairs Drug Disposition.
Périodique
Journal of the American Society of Nephrology : JASN
Auteur(s)
Nikolaeva S., Ansermet C., Centeno G., Pradervand S., Bize V., Mordasini D., Henry H., Koesters R., Maillard M., Bonny O., Tokonami N., Firsov D.
ISSN
1533-3450 (Electronic)
ISSN-L
1046-6673
Statut éditorial
Publié
Date de publication
10/2016
Peer-reviewed
Oui
Volume
27
Numéro
10
Pages
2997-3004
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question, we performed a combined functional, transcriptomic, and metabolomic analysis in mice with inducible conditional knockout (cKO) of BMAL1, which is critically involved in the circadian clock system, in renal tubular cells (Bmal1(lox/lox)/Pax8-rtTA/LC1 mice). Induction of cKO in adult mice did not produce obvious abnormalities in renal sodium, potassium, or water handling. Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport in cKO mice compared with control littermates. Furthermore, kidneys from cKO mice exhibited a significant decrease in the NAD(+)-to-NADH ratio, which reflects the oxidative phosphorylation-to-glycolysis ratio and/or the status of mitochondrial function. Metabolome profiling showed significant changes in plasma levels of amino acids, biogenic amines, acylcarnitines, and lipids. In-depth analysis of two selected pathways revealed a significant increase in plasma urea level correlating with increased renal Arginase II activity, hyperargininemia, and increased kidney arginine content as well as a significant increase in plasma creatinine concentration and a reduced capacity of the kidney to secrete anionic drugs (furosemide) paralleled by an approximate 80% decrease in the expression level of organic anion transporter 3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at the intrarenal and systemic levels and are involved in drug disposition.

Pubmed
Web of science
Open Access
Oui
Création de la notice
25/04/2016 8:02
Dernière modification de la notice
20/08/2019 13:24
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