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

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, ET(A) and ET(B). 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, ET(A) and ET(B) 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, ET(A) and ET(B) exhibited peaks of expression in opposite circadian phases. In contrast, expressions of ET-1, ET(A) and ET(B) 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 ET(A), but not ET(B), 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.