Table 3. Loss-of-function (LOF) approaches investigating the role of the brain PRR in the regulation of BP.

Biological System	Cellular/Neuroanatomical Location	LOF Strategy	Main Results	Ang II-Dependent or Independent effects	Refs.
Rat	SON	Microinjection of AAV-PRR-shRNA	• Decreases MAP, HR, and plasma AVP levels.	No	[134]
Mouse	SFO	ICV injection of AAV-PRR-shRNA	• Decreases MAP, vasomotor and cardiac sympathetic tone, and increases baroreflex sensitivity, and AVP level.	Reduction in AT1R	[96]
Rat	NTS	Microinjection of AAV-PRR-shRNA	• Increases MAP, impairs baroreflex sensitivity, and attenuates inflammation in SHR rats. • Renin microinjection decreases MAP and HR in SHR but not WKY rats. • Prorenin treatment in primary neurons induces NF-κB activation and increases mRNA expression of proinflammatory cytokines.	Ang II-independent cytokine signaling	[107]
Mouse	Neurons	Cre-loxp system: Deletion of PRR by Cre recombinase driven by pan neuronal neurofilament heavy chain promoter (Nefh-PRR KO)	• ICV infusion of mouse prorenin induces an elevation of BP that is blocked by neuronal PRR deletion. • PRR deletion decreases Ang II levels in the cortex, hypothalamus, and brainstem of DOCA-salt mice. • PRR knockdown attenuates the development of DOCA-salt hypertension and improves autonomic function.	Ang II formation in the CNS	[24]
Mouse	Neurons		• PRR deletion decreases salt appetite, fluid intake, urine volume, and sodium levels induced by DOCA.	No	[140]
Mouse	Neurons		• Prorenin acts via the PRR to increase the excitability of magnocellular neurons in the SON. • Prorenin-PRR signaling contributes to increased AVP levels in DOCA-salt mice.	No	[76]
Mouse	Neurons		• HFD increases prorenin levels in the plasma and hypothalamus. • HFD increases Ang II level in the hypothalamus; PRR deletion decreases Ang II levels in the hypothalamus. • PRR deletion attenuates obesity-induced hypertension and diabetes. • PRR deletion attenuates HFD-induced astrogliosis, and astrocytic and neuronal NF-κB p65 activation in the Arc.	Ang II formation in the CNS	[71]
Mouse	PVN neuron	Bilateral microinjection of AAV2-Cre virus into the PVN of PRR-loxP mice.	• PRR knockdown in PVN neurons attenuates the development of DOCA-salt hypertension. • PRR knockdown reduces ERK1/2 activation in PVN and RVLM neurons. • PRR knockdown reduces AT1 expression (mRNA) and attenuates AT1-dependent Ca2+ activity in the PVN.	Ang II-dependent and -independent ERK1/2 activation and Ca2+ activity	[70]

Abbreviations: AAV-PRR-shRNA, adeno-associated virus encoding shRNA against the PRR; AAV-Cre, adeno-associated virus encoding Cre recombinase; Ang II, angiotensin II; AT₁, angiotensin II type 1 receptor; AVP, arginine vasopressin; DOCA, deoxycorticosterone; ERK1/2, extracellular signal-regulated kinase 1/2; HFD, high-fat diet; HR, heart rate; HTN, hypertensive; ICV, intracerebroventricular; MAP, mean arterial pressure; mRenin, mouse renin; NF-κB, nuclear factor-κB; NTS, nucleus tractus solitarius; PVN, paraventricular nucleus; RA, renin angiotensinogen mice; RVLM, rostral ventrolateral medulla; SFO, subfornical organ; SHR, spontaneously hypertensive rat; SON, supraoptic nucleus; WKY, Wistar Kyoto rat; WT, wild type.