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Review
. 2024 Dec 11;25(24):13284.
doi: 10.3390/ijms252413284.

An Overview on Renal and Central Regulation of Blood Pressure by Neuropeptide FF and Its Receptors

Hewang Lee  1 , Jun B Feranil  1 , Pedro A Jose  1   2
Affiliations
Review

An Overview on Renal and Central Regulation of Blood Pressure by Neuropeptide FF and Its Receptors

Hewang Lee et al. Int J Mol Sci. .

Abstract

Neuropeptide FF (NPFF) is an endogenous octapeptide that was originally isolated from the bovine brain. It belongs to the RFamide family of peptides that has a wide range of physiological functions and pathophysiological effects. NPFF and its receptors, NPFFR1 and NPFFR2, abundantly expressed in rodent and human brains, participate in cardiovascular regulation. However, the expressions of NPFF and its receptors are not restricted within the central nervous system but are also found in peripheral organs, including the kidneys. Both NPFFR1 and NPFFR2 mainly couple to Gαi/o, which inhibits cyclic adenosine monophosphate (cAMP) production. NPFF also weakly binds to other RFamide receptors and the Mas receptor. Relevant published articles were searched in PubMed, Google Scholar, Web of Science, and Scopus. Herein, we review evidence for the role of NPFF in the regulation of blood pressure, in the central nervous system, particularly within the hypothalamic paraventricular nucleus and the brainstem, and the kidneys. NPFF is a potential target in the treatment of hypertension.

Keywords: NPFF receptor 1 (NPFFR1); NPFF receptor 2 (NPFFR2); blood pressure; brainstem; hypothalamus; kidney; neuropeptide FF (NPFF); paraventricular nucleus.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic diagram of NPFF expression associated with blood pressure regulation in the central nervous system (CNS). In situ hybridization shows that NPFF is mainly expressed in mouse caudal brainstem and spinal cord [28], presumably including the NTS, RVLM, CVLM, and nucleus Amb (in blue); additional expression is also reported in PVN, SON, VMH, and DMH using in situ hybridization [27] and immunohistochemistry (in green) [30]. NPFF is highly expressed in the spinal cord (mainly in the dorsal horn) in rats, mice, and humans [27,28,29,30]. In mice, NPFFR1 is expressed in multiple hypothalamic nuclei, including the PVN, SON, ARC, OVLT, and VMH and non-hypothalamic regions, such as HP and CTX. NPFFR2 is widely and highly expressed in hypothalamic nuclei, including the OVLT, SON, PVN, ARC, and VMH, and in non-hypothalamic regions such as the HP, Pir, and CTX [36]. In humans, NPFF is also expressed in the gray matter of the frontal, cingulate, superior temporal gyri, and superficial white matter in human brains [32]. NPFF and its receptors play an important role in the regulation of blood pressure, presumably involving baroreflex, sympathetic, parasympathetic (vagal), and neuroendocrine mechanisms. Amb, nucleus ambiguus; ARC, arcuate nucleus; CTX, cerebral cortex; CVLM, caudal ventrolateral medulla; DMH, dorsomedial hypothalamus; HP, hippocampus; NTS, nucleus tractus solitarius; OVLT, organum vasculosum of the lamina terminalis; Pir, piriform cortex; PVN, paraventricular nucleus; RVLM, rostroventrolateral medulla; SON, supraoptic nucleus; SpV, spinal trigeminal nucleus; VMH, ventromedial hypothalamus. Of note, the diagram is depicted in human brain, assuming NPFF expression is highly conserved in rodents and humans.
Figure 2
Figure 2
Schematic diagram of NPFF and its receptors’ signaling pathways. NPFF binds to NPFFR1, NPFFR2, MasR, and other RFamide receptors. NPFFR1 and NPFFR2 are primarily coupled to inhibitory Gαi/o and inhibit adenylate cyclase activity. NPFFR2 can also couple to Gαs and stimulate adenylate cyclase activity in the mouse cerebellum, olfactory bulb, and spinal cord. NPFF weakly binds to MasR, activating an atypical Gαq-phospholipase C signaling pathway. The thick arrows show the principal mechanisms of NPFFR1 and NPFFR2 activation, while the thin arrows show ancillary mechanisms of NPFFR2 activation.
Figure 3
Figure 3
Hypothetical CNS-mediated regulation of blood pressure by NPFF. NPFF regulates blood pressure via its receptors NPFFR1 and NPFFR2 in the hypothalamus, the brainstem, limbic system, and spinal cord through the hypothalamus–pituitary–adrenal (HPA) axis, baroreceptor reflex, GABAergic, muscarinic, α- and β-adrenergic, serotoninergic, dopaminergic, and NMDAergic systems. The chronic increase in corticotropin-releasing hormone signaling associated with dysregulated signaling of the HPA axis increases the cortisol levels and, subsequently, blood pressure. In concert with the release of catecholamines, sympathetic activity is increased, whereas parasympathetic activity is decreased, resulting in an increase in blood pressure. HPA, hypothalamic–pituitary–adrenal axis; PVN, periventricular nucleus of the hypothalamus; NMDA, N-methyl-D-aspartic acid.
Figure 4
Figure 4
NPFF-mediated regulation of blood pressure in the kidney. The genes and proteins of NPFF and its receptors, NPFFR1 and NPFFR2, are expressed in human and mouse kidneys. NPFF decreases forskolin-stimulated cAMP production. The renal subcapsular infusion of NPFF in C57BL/6 mice decreases renal sodium excretion and increases blood pressure. These findings suggest that NPFF and its receptors in the kidney increase renal sodium transport and subsequently blood pressure, but the mechanisms involved remain to be determined.
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