Lbrecht et al., 2001; Schmutz et al., 2010). Lamia et al. have shown that other circadian clock proteins, Cry1 and Cry2, can interact together with the GR, bind to the glucocorticoid response element inside the phosphoenolpyruvatecarboxykinase 1 promoter, and subsequently repress GR action (Lamia et al., 2011). These earlier research provided precedent for coordinate action of MR and Per1 on transcriptional regulation of ENaC. The circadian clock plays a crucial function in the handle of BP and renal function (Richards and Gumz, 2013). CLOCK KO mice have lower BP, Stearoyl-CoA Desaturase (SCD) custom synthesis dysregulated sodium excretion (Zuber et al., 2009) plus the loss of circadian expression of plasma aldosterone levels (Nikolaeva et al., 2012). BMAL1 KO mice exhibit lowered BP in the course of the active phase (Curtis et al., 2007). Cry1/Cry2 KO mice exhibit salt sensitive hypertension as a consequence of an up-regulation in the aldosterone synthesis enzyme 3–dehydrogenase-isomerase leading to elevated aldosterone synthesis and high aldosterone levels (Doi et al., 2010). Each the CLOCK KO and Cry1/Cry2 KO phenotypes and their dysregulated aldosterone levels offer added proof of a connection among the circadian clock and aldosterone signaling. Collectively with our finding that Per1 is an early aldosterone target (Gumz et al., 2003), the present study demonstrates that MR and Per1 interact with E-boxes inside the ENaC promoter. These data give additional evidence for the function on the circadian clock in aldosterone signaling. The coordinated action of MR and Per1 might recommend a previously unrecognized mechanism by which the circadian clock modulates physiological rhythms and aldosterone signaling.ACKNOWLEDGMENTSThe authors would prefer to thank Dr. Brian Cain and Dr. Mollie Jacobs for important overview of this manuscript. This function was supported by NIH DK085193 and DK098460 to Michelle L. Gumz, and AHA Predoctoral fellowship 13PRE16910096 to Jacob Richards.Dibner, C., Schibler, U., and Albrecht, U. (2010). The mammalian circadian timing method: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517?49. doi: 10.1146/annurev-physiol021909-135821 Doi, M., Takahashi, Y., Komatsu, R., Yamazaki, F., Yamada, H., Haraguchi, S., et al. (2010). Saltsensitive hypertension in circadian clock-deficient Cry-null mice entails dysregulated adrenal Hsd3b6. Nat. Med. 16, 67?four. doi: ten.1038/nm.2061 Gumz, M. L., Cheng, K. Y., Lynch, I. J., Stow, L. R., Greenlee, M. M., Cain, B. D., et al. (2010). Regulation of alphaENaC expression by the circadian clock protein Period 1 in mpkCCD(c14) cells. Biochim. Biophys. Acta 1799, 622?29. doi: 10.1016/j.bbagrm.2010.09.003 Gumz, M. L., Popp, M. P., Wingo, C. S., and Cain, B. D. (2003). Early transcriptional effects of aldosterone in a mouse inner medullary collecting duct cell line. Am. J. Physiol. Renal Physiol. 285, F664 673. Gumz, M. L., Stow, L. R., Lynch, I. J., Greenlee, M. M., Rudin, A., Cain, B. D., et al. (2009). The circadian clock protein Period 1 regulates expression of your renal epithelial sodium channel in mice. J. Clin. Invest. 119, 2423?434. doi: 10.1172/JCI36908 Kohn, J. A., Deshpande, K., and Ortlund, E. A. (2012). Deciphering modern glucocorticoid crosspharmacology making use of ancestral corticosteroid receptors. J. Biol. Chem. 287, 16267?6275. doi: 10.1074/jbc.M112.346411 Kucera, N., Schmalen, I., Hennig, S., Ollinger, R., Strauss, H. M., Grudziecki, A., et al. (2012). Unwinding the Caspase 1 custom synthesis variations in the mammalian PERIOD clock proteins from cryst.