title: Nephron-Specific Deletion of Circadian Clock Gene Bmal1 Alters the Plasma and Renal Metabolome and Impairs Drug Disposition.
abstract: 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 (Bmal1lox/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.
authors.affiliation: Department of Pharmacology and Toxicology and Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Nikolaeva
authors.affiliation: Department of Pharmacology and Toxicology and.
authors.forename: Camille
authors.initials: C
authors.lastname: Ansermet
authors.affiliation: Department of Pharmacology and Toxicology and.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Centeno
authors.affiliation: Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.affiliation: Department of Pharmacology and Toxicology and.
authors.forename: Vincent
authors.initials: V
authors.lastname: Bize
authors.affiliation: Department of Pharmacology and Toxicology and Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Mordasini
authors.affiliation: Service of Biomedicine and.
authors.forename: Hugues
authors.initials: H
authors.lastname: Henry
authors.affiliation: Department of Nephrology, Tenon Hospital, Université Pierre et Marie Curie, Paris, France; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Koesters
authors.affiliation: Service of Nephrology, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Maillard
authors.affiliation: Department of Pharmacology and Toxicology and Service of Nephrology, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonny
authors.affiliation: Department of Pharmacology and Toxicology and Labeled Research Team (ERL) 8228-U1138 équipe 3, Centre de Recherche des Cordeliers, Paris, France natsuko.tokonami@crc.jussieu.fr dmitri.firsov@unil.ch.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tokonami
authors.affiliation: Department of Pharmacology and Toxicology and natsuko.tokonami@crc.jussieu.fr dmitri.firsov@unil.ch.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Firsov
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000818:Animals; D057906:Circadian Clocks / Q000235:genetics*; D004232:Diuretics / Q000097:blood / Q000378:metabolism*; D005665:Furosemide / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D055442:Metabolome / Q000235:genetics*; D051379:Mice; D009399:Nephrons
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D004232:Diuretics; D005665:Furosemide
keywords: arginase; circadian clock; kidney excretory rhythms; metabolome; organic anion transporter