Neuronal Cilia in Hypertension

University Of Iowa, Iowa City IA

Investigators

Abstract

Project Summary / Abstract Hypertension is an important public health challenge in the United States due to its high prevalence and strong association with stroke, myocardial infarction, congestive heart failure, and end-stage renal diseases. Although effective therapies for hypertension exist, many adults with hypertension remain resistant to treatment. This makes hypertension an important medical and public health issue and highlight the need to identify new mechanisms of hypertension. The cilium is an evolutionary conserved organelle that serve as a sensor of extracellular cues and the transduction of those cues into cellular signaling ultimately affecting a wide range of cellular and physiological processes. The goal of this project is to study the role of neuronal primary cilia in hypertension, autonomic dysfunction and body fluid imbalance. We recently discovered that neuronal primary cilia regulate blood pressure and that hypertensive animals display abnormally elongated cilia in the supraoptic nucleus, a key brain nucleus for blood pressure and fluid homeostasis. We also uncovered a novel role for the renin-angiotensin system in the control of primary cilia. Based on these exciting findings, we propose to test the novel hypothesis that neuronal primary cilia contribute to hypertension, fluid imbalance and sympathetic nerve activation through a mechanism that involve Angiotensin II type 1a receptor (AT1aR) signaling. We will evaluate how conditional ablation of cilia in the supraoptic nucleus affects blood pressure, drinking, urine volume, sodium concentration, plasma osmolality regional sympathetic nerve traffic and neuronal activity in hypertensive mice. We will also examine how these parameters are affected by AT1aR deficiency in the supraoptic nucleus. Finally, we will probe the mechanisms underlying cilia regulation by the AT1aR. The current proposal should fundamentally advance our understanding of the neuronal mechanisms that mediate regulation of blood pressure, sympathetic traffic and body fluid balance in health and disease. Insights into these mechanisms may make it possible to selectively interfere with the hypertension and other cardiovascular risks.