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
(Pro)renin receptor knockdown in the paraventricular nucleus of the hypothalamus attenuates hypertension development and AT1 receptor-mediated calcium events
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Media type:
E-Article
Title:
(Pro)renin receptor knockdown in the paraventricular nucleus of the hypothalamus attenuates hypertension development and AT1 receptor-mediated calcium events
Contributor:
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
imprint:
American Physiological Society, 2019
Published in:American Journal of Physiology-Heart and Circulatory Physiology
Description:
<jats:p> 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<jats:sup>2+</jats:sup> biosensor GCaMP6 to monitor Ca<jats:sup>2+</jats:sup>-signaling events in the neurons of PVN brain slices, we identified a reduction in angiotensin II type 1 receptor-mediated Ca<jats:sup>2+</jats:sup> 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<jats:sup>2+</jats:sup> activity. </jats:p><jats:p> NEW & NOTEWORTHY 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<jats:sub>1a</jats:sub>R expression and AT<jats:sub>1</jats:sub>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. </jats:p>