Table 2.

Gain-of-function (GOF) approaches investigating the role of the brain PRR in the regulation of BP.

Biological System	Cellular/Neuroanatomical Location	GOF Strategy	Main Results	Ang II-Dependent or Independent Effects Investigated?	Refs.
Rat	SON WKY brain neurons	Microinjection of AAV-hPRR.	• hPRR overexpression decreases water intake and urine excretion. • hPRR overexpression increases urine osmolality, plasma and urine AVP levels.	Ang II formation in primary culture WKY brain neurons	[134]
Cell culture	Neuro-2A cells	Infected N2A cells with AAV-hPRR	• hPRR overexpression increases Ang II levels, ERK1/2 and Akt phosphorylation, and ROS. • PI3K and MAPK inhibition attenuate oxidative stress caused by hPRR overexpression.	Ang II generation and Ang II-independent MAPK signal pathways	[102]
Mouse	All neurons	Transgenic overexpression of hPRR driven by rat synapsin1 promoter	• ICV infusion of human prorenin induces Ang II-independent BP elevation. • ERK1/2 activation downstream of prorenin/PRR signaling is key to NOX4 activation, oxidative stress and ANG II-independent hypertension.	Ang II-independent ERK1/2, NOX4, and oxidative stress activation	[75]

Abbreviations: AAV-hPRR, adeno-associated virus encoding human PRR; Akt, protein kinase B; Ang II, angiotensin II; AVP, arginine vasopressin; ERK1/2, signal-regulated kinase 1/2; ICV, intracerebroventricular; MAPK, mitogen-activated protein kinase; N2A, Neuro-2A cells; NOX, NADPH oxidase; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; PVN, paraventricular nucleus; RA, renin angiotensinogen mice; ROS, reactive oxygen species; SD, Sprague-Dawley; SHR, spontaneously hypertensive rats; SON, supraoptic nucleus.