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, 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 Pert 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 Peni heterozygous mice. Interestingly. ET-1 and ETA, but not ETB. were expressed in a time-dependent manner in the heart. Significance: Pen 1 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. (C) 2014 Published by Elsevier Inc.