Cardiovascular disease is the leading cause of death in the United States and hypertension is the principal risk factor for this mortality. Nearly one-third of Americans are hypertensive, and the majority of these individuals have essential hypertension, which denotes the lack of a defined etiology. Circadian fluctuations in blood pressure and cardiac function are well-documented. Cardiovascular events such as stroke and myocardial infarction are known to peak with a circadian pattern and have been linked to the morning increase in blood pressure and heart rate. Indeed, many physiological processes exhibit a circadian pattern, including the sleep- wake cycle, heartbeat, hormone secretion, and renal function. However, the role of the circadian clock in the regulation of these processes is not understood at a molecular level. The long term goal of these studies is to characterize the role of the circadian clock in hypertension and cardiovascular disease. Understanding these mechanisms could lead to new disease treatments. We have found that the circadian clock protein Per1 regulates the expression of the rate-limiting ? subunit of the renal epithelial sodium channel. Our recently published data demonstrate a role for Per1 in the coordinate regulation of several additional genes that code for proteins that contribute to the regulation of renal sodium reabsorption. Per1 positively regulates genes whose products increase sodium reabsorption, and negatively regulates genes whose products inhibit sodium reabsorption. These data led us to hypothesize that Per1 action results in induction of renal sodium reabsorption with consequent increases in plasma volume and blood pressure. Consistent with this hypothesis, we have shown that mice lacking functional Per1 have dramatically lower blood pressure compared to wild type mice. Taken together, these novel findings support our central hypothesis that Per1, as part of the circadian clock mechanism, regulates blood pressure via a renal sodium-dependent mechanism. The goal of this proposal is to test our hypothesis through two specific aims. In the first aim, we will use a pharmacological inhibitor of Per1 nuclear entry and evaluate the effect of this treatment on the expression of Per1 target genes and blood pressure. These studies will determine if Per1 is a viable target for controlling blood pressure. In the second aim, we will develop a kidney-specific Per1 knockout mouse to test the role of Per1 in the regulation of blood pressure by the kidney. These studies have the potential to identify a novel target for the treatment of hypertension and will yield insight into the mechanism of how the circadian clock contributes to the regulation of blood pressure.
Many important physiological processes such as blood pressure and kidney function display a circadian rhythm, but the link between these processes and the circadian clock is not understood. Our data demonstrate a role for the circadian clock protein Per1 in the regulation of blood pressure. The goals of this application are to target Per1 as a treatment for hypertension and to generate an animal model to define the role of Per1 in the regulation of blood pressure by the kidney.
|Richards, Jacob; Ko, Benjamin; All, Sean et al. (2014) A role for the circadian clock protein Per1 in the regulation of the NaCl co-transporter (NCC) and the with-no-lysine kinase (WNK) cascade in mouse distal convoluted tubule cells. J Biol Chem 289:11791-806|
|Richards, Jacob; Diaz, Alexander N; Gumz, Michelle L (2014) Clock genes in hypertension: novel insights from rodent models. Blood Press Monit 19:249-54|
|Gumz, Michelle L (2014) Molecular origin of the kidney clock. Kidney Int 86:873-4|