Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1

Apr 12, 2014Life sciences

How the daily clock protein Per1 controls the endothelin system differently across tissues and times

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Abstract

Reduced Per1 expression significantly decreases ET-1 levels in the lung of Per1 heterozygous mice.

The regulation of endothelin axis gene expression is tissue-specific and varies with circadian rhythms.
In the renal inner medulla and liver, ETA and ETB mRNAs peak at opposite times of day.
ET-1, ETA, and ETB expressions in the lung remain constant throughout the day, with a marked decrease in Per1 heterozygous mice.
In the heart, ET-1 and ETA show time-dependent expression, while ETB does not.
These findings suggest that the timing of endothelin receptor antagonist administration may be important.

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AIMS: 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.

MAIN 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.

KEY FINDINGS: 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.

SIGNIFICANCE: 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.

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Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1

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