(Pro)renin receptor knockdown in the paraventricular nucleus of the hypothalamus attenuates hypertension development and AT receptor-mediated calcium events.

Authors:
Caleb J Worker
Caleb J Worker
Center for Cardiovascular Research
Wencheng Li
Wencheng Li
Tulane University School of Medicine
United States
Fatima Trebak
Fatima Trebak
Laboratory of Neuroendocrinology & Nutritional and climatic Environment
Trevor Watkins
Trevor Watkins
Princess Alexandra Hospital
Woolloongabba | Australia
Evan Yamasaki
Evan Yamasaki
University of Nevada School of Medicine
Silvana G Cooper
Silvana G Cooper
and Cell Biology; Center for Cardiovascular Research

Am J Physiol Heart Circ Physiol 2019 Jun 29;316(6):H1389-H1405. Epub 2019 Mar 29.

Department of Pharmacology, University of Nevada, Reno, School of Medicine , Reno, Nevada.

Activation of the brain renin-angiotensin system (RAS) is a pivotal step in the pathogenesis of hypertension. The paraventricular nucleus (PVN) of the hypothalamus is a critical part of the angiotensinergic sympatho-excitatory neuronal network involved in neural control of blood pressure and hypertension. However, the importance of the PVN (pro)renin receptor (PVN-PRR)-a key component of the brain RAS-in hypertension development has not been examined. In this study, we investigated the involvement and mechanisms of the PVN-PRR in DOCA-salt-induced hypertension, a mouse model of hypertension. Using nanoinjection of adeno-associated virus-mediated Cre recombinase expression to knock down the PRR specifically in the PVN, we report here that PVN-PRR knockdown attenuated the enhanced blood pressure and sympathetic tone associated with hypertension. Mechanistically, we found that PVN-PRR knockdown was associated with reduced activation of ERK (extracellular signal-regulated kinase)-1/2 in the PVN and rostral ventrolateral medulla during hypertension. In addition, using the genetically encoded Ca biosensor GCaMP6 to monitor Ca-signaling events in the neurons of PVN brain slices, we identified a reduction in angiotensin II type 1 receptor-mediated Ca activity as part of the mechanism by which PVN-PRR knockdown attenuates hypertension. Our study demonstrates an essential role of the PRR in PVN neurons in hypertension through regulation of ERK1/2 activation and angiotensin II type 1 receptor-mediated Ca activity. PRR knockdown in PVN neurons attenuates the development of DOCA-salt hypertension and autonomic dysfunction through a decrease in ERK1/2 activation in the PVN and RVLM during hypertension. In addition, PRR knockdown reduced ATR expression and ATR-mediated calcium activity during hypertension. Furthermore, we characterized the neuronal targeting specificity of AAV serotype 2 in the mouse PVN and validated the advantages of the genetically encoded calcium biosensor GCaMP6 in visualizing neuronal calcium activity in the PVN.

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http://dx.doi.org/10.1152/ajpheart.00780.2018DOI Listing
June 2019
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