Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1.
OBJECTIVE
The present study is designed to consider a role for the circadian clock protein Per1 in the regulation of the endothelin axis in mouse kidney, lung, liver and heart. Renal endothelin-1 (ET-1) is a regulator of the epithelial sodium channel (ENaC) and blood pressure (BP), via activation of both endothelin receptors, ETA and ETB. However, ET-1 mediates many complex events in other tissues.


METHODS
Tissues were collected in the middle of murine rest and active phases, at noon and midnight, respectively. ET-1, ETA and ETB mRNA expressions were measured in the lung, heart, liver, renal inner medulla and renal cortex of wild type and Per1 heterozygous mice using real-time quantitative RT-PCR.


RESULTS
The effect of reduced Per1 expression on levels of mRNAs and the time-dependent regulation of expression of the endothelin axis genes appeared to be tissue-specific. In the renal inner medulla and the liver, ETA and ETB exhibited peaks of expression in opposite circadian phases. In contrast, expressions of ET-1, ETA and ETB in the lung did not appear to vary with time, but ET-1 expression was dramatically decreased in this tissue in Per1 heterozygous mice. Interestingly, ET-1 and ETA, but not ETB, were expressed in a time-dependent manner in the heart.


CONCLUSIONS
Per1 appears to regulate expression of the endothelin axis genes in a tissue-specific and time-dependent manner. These observations have important implications for our understanding of the best time of day to deliver endothelin receptor antagonists.
Department of Medicine, University of Florida, USA; Department of Biochemistry and Molecular Biology, University of Florida, USA.
Jacob
J
Richards
Department of Medicine, University of Florida, USA; North Florida/South Georgia Veterans Health System, Gainesville, FL, USA.
Amanda K
AK
Welch
Department of Medicine, University of Florida, USA; Department of Biochemistry and Molecular Biology, University of Florida, USA.
Sarah J
SJ
Barilovits
Department of Medicine, University of Florida, USA.
Sean
S
All
Department of Medicine, University of Florida, USA.
Kit-Yan
KY
Cheng
Department of Medicine, University of Florida, USA; North Florida/South Georgia Veterans Health System, Gainesville, FL, USA.
Charles S
CS
Wingo
Department of Biochemistry and Molecular Biology, University of Florida, USA.
Brian D
BD
Cain
Department of Medicine, University of Florida, USA; Department of Biochemistry and Molecular Biology, University of Florida, USA. Electronic address: Michelle.Gumz@medicine.ufl.edu.
Michelle L
ML
Gumz
D000818:Animals; D057906:Circadian Clocks / Q000235:genetics; D019332:Endothelin-1 / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity / Q000235:genetics; D056950:Period Circadian Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013997:Time Factors
D019332:Endothelin-1; D016232:Endothelins; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
ETA; ETB; Endothelin-A receptor; Endothelin-B receptor; Gene regulation