Exacerbated effects of prorenin on hypothalamic magnocellular neuronal activity and vasopressin plasma levels during salt-sensitive hypertension

Abstract

Accumulating evidence supports that the brain renin-angiotensin system (RAS), including prorenin (PR) and its receptor (PRR), two newly discovered RAS players, contribute to sympathoexcitation in salt-sensitive hypertension. Still, whether PR also contributed to elevated circulating levels of neurohormones such as vasopressin (VP) during salt-sensitive hypertension, and if so, what are the precise underlying mechanisms, remains to be determined. To address these questions, we obtained patch-clamp recordings from hypothalamic magnocellular neurosecretory neurons (MNNs) that synthesize the neurohormones oxytocin and VP in acute hypothalamic slices obtained from sham and deoxycorticosterone acetate (DOCA)-salt-treated hypertensive rats. We found that focal application of PR markedly increased membrane excitability and firing responses in MNNs of DOCA-salt, compared with sham rats. This effect included a shorter latency to spike initiation and increased numbers of spikes in response to depolarizing stimuli and was mediated by a more robust inhibition of A-type K+ channels in DOCA-salt compared with sham rats. On the other hand, the afterhyperpolarizing potential mediated by the activation of Ca2+-dependent K+ channel was not affected by PR. mRNA expression of PRR, VP, and the Kv4.3 K+ channel subunit in the supraoptic nucleus of DOCA-salt hypertensive rats was increased compared with sham rats. Finally, we report a significant decrease of plasma VP levels in neuron-selective PRR knockdown mice treated with DOCA-salt, compared with wild-type DOCA-salt-treated mice. Together, these results support that activation of PRR contributes to increased excitability and firing discharge of MNNs and increased plasma levels of VP in DOCA-salt hypertension. NEW & NOTEWORTHY Our studies support that prorenin (PR) and its receptor (PRR) within the hypothalamus contribute to elevated plasma vasopressin levels in deoxycorticosterone acetate-salt hypertension, in part because of an exacerbated effect of PR on magnocellular neurosecretory neuron excitability; Moreover, our study implicates A-type K+ channels as key underlying molecular targets mediating these effects. Thus, PR/PRR stands as a novel therapeutic target for the treatment of neurohumoral activation in salt-sensitive hypertension.

Increased (Pro)renin Receptor Expression in the Hypertensive Human Brain

“…PVN is a part of Ang II-sensitive neural circuits (Chen and Toney, 2003;Cato and Toney, 2005;Knight et al, 2013) that receive excitatory projections from circumventricular organs in the forebrain; excitatory neurons in this brain nucleus projects to the RVLM, activating sympathetic premotor C1 neurons and increasing sympathetic activity and BP (Tagawa and Dampney, 1999;Li et al, 2003). Previous studies have demonstrated expression of the PRR in the PVN and established its role in the regulation of sympathetic activity and vasopressin secretion in NTN and HTN animals (Huber et al, 2015;Pitra et al, 2016Pitra et al, , 2019Souza et al, 2019). PRR expression is also upregulated in the hypothalamus of HTN mice (Li et al, 2015a).…”

An Angiotensin-Responsive Connection from the Lamina Terminalis to the Paraventricular Nucleus of the Hypothalamus Evokes Vasopressin Secretion to Increase Blood Pressure in Mice

“…Excitation of these presympathetic neurons increases blood pressure by augmenting sympathetic outflow (Tucker and Saper, 1985;Coote et al, 1998;Cato and Toney, 2005). Stimulation of the RAS and, in particular, AT1aRs within the brain is heavily linked to AVP release and sympathetic outflow that increases blood pressure (Lo n et al, 1996;Marciante et al, 2019;Pitra et al, 2019); and because the PVN expresses AT1aR, a predominating hypothesis has been that Ang-II acts directly on AVP-containing and preautonomic neurons to drive these responses. However, increasing evidence demonstrates that such neurons do not themselves express angiotensin receptors (Lenkei et al, 1995;Oldfield et al, 2001).…”

(Pro)renin receptor signaling in hypothalamic tyrosine hydroxylase neurons is required for obesity-associated glucose metabolic impairment

“…In addition to the local generation of Ang II, which binds to and activates neuronal angiotensin receptors, binding of the PRR by either of its 2 endogenous ligands (prorenin or renin) activates an intracellular tyrosine kinase signal transduction cascade (16,47). Interestingly, while activation of neuronal PRR signaling has been shown to promote hypertension development by increasing vasopressin release (30,32,48,49), we report that only a small percentage of PVN TH neurons express vasopressin. Indeed, our work suggests little, if any, role of PRR signaling in PVN TH neurons in cardiovascular regulation.…”

“…Expression of the PRR and vasopressin by PVN TH neurons in mice. Prr mRNA and PRR protein are expressed by neurons in both the rodent and human brain (30,31), including presympathetic and vasopressin-containing neurons in the PVN (32,33). To determine if either PRR or vasopressin are expressed in PVN TH neurons, we used RNAScope in situ hybridization.…”