Modulation of the renal aldosterone endothelin feedback system by the clock protein PER1

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Project Summary: Elevated aldosterone levels and high salt diets contribute to the epidemics of hypertension and kidney disease. This is in part due to dysregulation of fluid and electrolyte balance within the kidney. The kidney plays a key role in the regulation of blood pressure (BP) through its homeostatic control of sodium (Na) and water balance by the distal nephron. This process is tightly regulated by the mineralocorticoid aldosterone and other intrinsic regulatory mechanisms, including the endothelin-1 (ET-1) signaling axis. We identified ET-1 as a novel aldosterone target. We also demonstrated that ET-1 acts in a feedback mechanism within the kidney collecting duct to inhibit Na reabsorption via signaling through both the ETRA and ETRB receptors. This intrinsic regulatory mechanism, the renal aldosterone endothelin feedback system (RAEFS), is required for normal BP regulation and Na homeostasis. The significance of this feedback system is illustrated by the dramatic effects caused by its disruption, which causes salt-sensitive hypertension and fluid retention. Clinically, ETRA/B blockers have shown efficacy in kidney disease, but fluid retention is a troubling side effect. We have identified the circadian clock protein PER1 as a critical component for BP regulation and renal Na homeostasis. We have shown that PER1 acts in a sex-specific manner to control Na balance and BP in the setting of salt-sensitive hypertension. We demonstrated that PER1 is a negative regulator of ET-1 expression, linking PER1 and the RAEFS. Using a model of salt-sensitive hypertension, we recently discovered that male kidney-specific (KS)-PER1 KO mice exhibit increased BP and inappropriate Na retention in response to a high salt diet plus an aldosterone analog. Importantly, KS-PER1 KO mice exhibit elevated levels of ET-1 in the kidney and urine. We also recently discovered a novel, long non-coding RNA that is antisense to the ET-1 gene, EDN1-AS. EDN1-AS is a positive regulator of ET-1. Our new data show that ET-1 and EDN1-AS are positively regulated by aldosterone but negatively regulated by PER1. Together these data support our overall hypothesis that PER1 maintains BP and Na balance through inhibiting the action of aldosterone to increase ET-1 in the kidney. We propose that this modulation of the RAEFS constitutes a new paradigm for feedback control of Na balance and BP. Aim 1 will utilize whole animal BP and Na balance studies in control and kidney- specific PER1 and ET-1 KO mice. Aim 2 will employ the isolated perfused collecting duct to test the effect of PER1 on ET-1-dependent renal tubular Na reabsorption. Aim 3 will use a unique cell model of the collecting duct with inducible overexpression of EDN1-AS to determine the mechanism by which PER1, aldosterone, and EDN1-AS regulate the ET-1 gene. We propose that understanding the circadian molecular regulation of ET-1 is the key to unlocking the difficulties associated with ET-receptor blockers. Completion of these studies will provide the mechanistic knowledge necessary to determine the feasibility of employing circadian precision medicine for the tailored treatment of salt-sensitive hypertension.