Renal and adrenal actions of the clock protein PER1 in salt-sensitive hypertension - Healthy individuals have strong circadian rhythms in blood pressure and kidney function. Loss of rhythms in blood pressure and renal function causes increased risk for death from cardiovascular disease. The underlying mechanisms of these effects have not been determined but may involve components of the circadian clock. Circadian rhythms in physiological function are driven by a molecular clock present in nearly every cell type. We have identified the molecular clock component PERIOD1 (PER1) as a critical regulator of BP and kidney function using preclinical rodent models. Studies in humans show that PER1 expression is significancy reduced in the kidneys of people with hypertension or kidney disease. Loss of PER1 in rodent models causes disrupted rhythms in blood pressure, increased blood pressure, and impaired renal function in a salt-dependent manner. Salt-sensitive hypertension and kidney disease are public health burdens and there is an urgent need to develop new therapies and improve existing treatments. Based on our published data and exciting new results generated for this proposal, the premise of this application is that increasing PER1 expression in the kidney can prevent salt-sensitive hypertension and kidney disease. A key gap in knowledge is the mechanism by which PER1 mediates its protective effects. We have identified aldosterone signaling through the mineralocorticoid receptor (MR) and endothelin-1 (ET-1) signaling as downstream PER1 targets. The aldosterone/MR and ET-1 pathways are known contributors to salt-sensitive hypertension and kidney disease. Our data demonstrate that loss of PER1 results in adrenal dysfunction as shown by increased production of aldosterone and renal dysfunction including increased expression of MR and ET-1 in the kidney. These data together with our published work support the central hypothesis of this proposal, that PER1 suppresses aldosterone/MR and ET-1 signaling to prevent salt-sensitive hypertension. In Aim 1, we will test the hypothesis that loss of PER1 causes increased aldosterone/MR and ET-1 signaling, leading to salt-sensitive hypertension and renal/adrenal function, using a combination of genetic and pharmacological approaches. In Aim 2, we will test the hypothesis that PER1 expression and activity in the kidney can prevent salt-sensitive hypertension and renal/adrenal dysfunction using a combination of genetic knockout with kidney cross-transplantation or gene therapy to manipulate PER1 expression in the kidney. Understanding the mechanisms by which PER1 mediates its effects on blood pressure and renal/adrenal function will fill a key gap in the field regarding how circadian clock components contribute to physiology and pathophysiology. These studies will also provide important preclinical data to address the premise of this work, that increasing PER1 expression is viable therapeutic option for treating salt-sensitive hypertension and renal/adrenal dysfunction.
