Molecular clock is involved in predictive circadian adjustment of renal function.
Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e., distal convoluted tubule (DCT) and connecting tubule (CNT) and the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf, and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, alphaENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms, and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function.
Zuber
Annie Mercier
AM
Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland.
Centeno
Gabriel
G
Pradervand
Sylvain
S
Nikolaeva
Svetlana
S
Maquelin
Lionel
L
Cardinaux
Léonard
L
Bonny
Olivier
O
Firsov
Dmitri
D
D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics; D051401:Aquaporin 4 / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D001683:Biological Clocks / Q000235:genetics*; D001794:Blood Pressure; D056926:CLOCK Proteins; D002940:Circadian Rhythm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004573:Electrolytes / Q000097:blood; D020869:Gene Expression Profiling; D007671:Kidney Concentrating Ability; D007684:Kidney Tubules / Q000378:metabolism* / Q000502:physiology; D007685:Kidney Tubules, Collecting / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014563:Urodynamics
D051399:Aquaporin 2; D051401:Aquaporin 4; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D056926:CLOCK Proteins; D004268:DNA-Binding Proteins; D004573:Electrolytes; D009419:Nerve Tissue Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C498260:Dbp protein, mouse; C490670:Hlf protein, mouse; C491259:Npas2 protein, mouse; C498262:Nr1d1 protein, mouse; C489491:Tef protein, mouse; C538944:Clock protein, mouse