Per1 and the kidney clock in hypertension

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Project Summary One-third of adult Americans are afflicted with hypertension, a principal risk factor for a number of mortalities, including cardiovascular disease and chronic kidney disease. The vast majority of hypertension remains uncontrolled, despite available therapies. There is a clear need to identify new targets for the treatment of hypertension. Increased risk for adverse cardiovascular outcomes is associated with disruption of the circadian rhythm of blood pressure (BP), particularly in the setting of hypertension. BP should decrease, or “dip”, at night when humans rest. Non-dipping hypertension is associated with negative cardiovascular outcomes such as stroke and kidney damage. Mechanisms underlying non-dipping hypertension are not understood but one candidate is the molecular circadian clock. The clock is comprised of several core transcription factors that regulate gene expression in nearly every cell type in the body. We have identified the circadian clock protein Per1 as an important regulator of gene expression in the kidney. The kidney plays a critical role in the regulation of sodium balance, blood volume, and therefore BP. Multiple sodium transporters, expressed throughout the renal nephron, contribute to these functions of the kidney. The kidney is responsive to the sodium-regulating mineralocorticoid hormone aldosterone. The sodium/chloride cotransporter (NCC) and the epithelial sodium channel (ENaC) are expressed in the aldosterone-sensitive distal nephron and the collecting duct and are key determinants of renal sodium reabsorption and BP. Per1 is unique among the clock proteins because it is regulated by aldosterone. Per1 is also a novel regulator of NCC, ENaC and Endothelin-1 (ET-1), a peptide hormone that negatively regulates ENaC activity. We discovered that loss of Per1 affects the salt-sensitivity of BP and disrupts the circadian rhythm of BP, resulting in non-dipping hypertension. Taken together, our results suggest that Per1 may be a new therapeutic target for modulating BP and support a role for Per1 and the molecular kidney clock in the regulation of sodium balance and BP rhythms. The goal of this application is to test the hypothesis that Per1 regulates BP rhythms and sodium homeostasis through the coordinate regulation of NCC, ENaC, and ET-1 in the kidney. We have developed a novel, kidney-specific Per1 knockout mouse model to test this hypothesis. Aims 1 and 2 are designed to define the contribution of ENaC and NCC to Per1 action on renal sodium reabsorption and BP, whereas Aim 3 will define the role of ET-1 and its receptors in this regulation. Completion of these studies will, for the first time, specifically define the contribution of Per1 and the kidney clock to regulation of renal sodium handling and BP in a model of salt- sensitive hypertension. The studies proposed here have important implications for our understanding of mechanisms underlying non-dipping hypertension.