(Pro)renin receptor knockdown in the paraventricular nucleus of the hypothalamus attenuates hypertension development and AT 1 receptor-mediated calcium events

• Published in: American journal of physiology. Heart and circulatory physiology 2019-06, Vol.316 (6), p.H1389-H1405
• Main Authors: Souza, Lucas A C, Worker, Caleb J, Li, Wencheng, Trebak, Fatima, Watkins, Trevor, Gayban, Ariana Julia B, Yamasaki, Evan, Cooper, Silvana G, Drumm, Bernard T, Feng, Yumei
• Format: Article
• Language: English
• Subjects: Animals; Autonomic Nervous System - metabolism; Autonomic Nervous System - physiopathology; Blood Pressure; Calcium Signaling; CX3C Chemokine Receptor 1 - genetics; CX3C Chemokine Receptor 1 - metabolism; Desoxycorticosterone Acetate; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Knockdown Techniques; Hypertension - enzymology; Hypertension - genetics; Hypertension - physiopathology; Hypertension - prevention & control; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Neurons - enzymology; Paraventricular Hypothalamic Nucleus - enzymology; Paraventricular Hypothalamic Nucleus - physiopathology; Phosphorylation; Proton-Translocating ATPases - deficiency; Proton-Translocating ATPases - genetics; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Receptors, Cell Surface - deficiency; Receptors, Cell Surface - genetics
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00780.2018

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 AT R expression and AT R-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.