Lbrecht et al., 2001; Schmutz et al., 2010). Lamia et al. have shown that other circadian clock proteins, Cry1 and Cry2, can interact with the GR, bind to the glucocorticoid response element within the phosphoenolpyruvatecarboxykinase 1 promoter, and subsequently repress GR action (Lamia et al., 2011). These earlier research supplied precedent for coordinate action of MR and Per1 on transcriptional regulation of ENaC. The circadian clock plays an important role in the control of BP and renal function (Richards and Gumz, 2013). CLOCK KO mice have lower BP, 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 reduced BP during the active phase (Curtis et al., 2007). Cry1/Cry2 KO mice exhibit salt sensitive hypertension on account 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). Both the CLOCK KO and Cry1/Cry2 KO phenotypes and their dysregulated aldosterone levels Necroptosis Compound provide further evidence of a connection amongst the circadian clock and aldosterone signaling. With each other with our discovering that Per1 is an early aldosterone target (Gumz et al., 2003), the present study demonstrates that MR and Per1 interact with E-boxes within the ENaC promoter. These data provide extra proof for the role from the circadian clock in aldosterone signaling. The coordinated action of MR and Per1 may perhaps recommend a previously unrecognized mechanism by which the circadian clock modulates physiological rhythms and aldosterone signaling.ACKNOWLEDGMENTSThe authors would like to thank Dr. Brian Cain and Dr. Mollie Jacobs for essential critique 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 technique: 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 includes dysregulated adrenal Hsd3b6. Nat. Med. 16, 67?4. doi: 10.1038/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 the 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 contemporary glucocorticoid crosspharmacology working with 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). GHSR Formulation Unwinding the variations with the mammalian PERIOD clock proteins from cryst.
