The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

Abstract

The systemic renin-angiotensin system (RAS) has long been recognized as a critically important system in blood pressure (BP) regulation. However, extensive evidence has shown that a majority of RAS components are also present in many tissues and play indispensable roles in BP regulation. Here, we review evidence that RAS components, notably including the newly identified (pro)renin receptor (PRR), are present in the brain and are essential for the central regulation of BP. Binding of the PRR to its ligand, prorenin or renin, increases BP and promotes progression of cardiovascular diseases in an angiotensin II-dependent and -independent manner, establishing the PRR a promising antihypertensive drug target. We also review the existing PRR blockers, including handle region peptide and PRO20, and propose a rationale for blocking prorenin/PRR activation as a therapeutic approach that does not affect the actions of the PRR in vacuolar H(+)-ATPase and development. Finally, we summarize categories of currently available antihypertensive drugs and consider future perspectives.

Keywords: (Pro)renin receptor; (Pro)renin receptor antagonists; Antihypertensive drugs; Brain; Hypertension; Prorenin.

Figure 1. Expression of the PRR in brain regions involved in BP regulation

(A) A schematic showing the key cardiovascular regulatory brain nuclei. (B) Brain tissues from C57Bl/6J mice were stained with antibodies against the mouse PRR (red), the neuronal marker NeuN (blue), and the astrocyte marker GFAP (green). PRR immunoreactivity is predominantly co-localized with NeuN in SFO, PVN, NTS, RVLM, and AP. Abbreviations: SFO, subfornical organ; PVN, paraventricular nucleus of the hypothalamus; NTS, nucleus of the tractus solitaries; RVLM, rostral ventrolateral medulla; AP, area posterma; SON, supraoptic nucleus; OVLT, organum vasculosum of the lamina terminalis; CVLM, caudal ventrolateral medulla; NA, nucleus accumbens; IML, intermediolateral nucleus; PRR, (pro)renin receptor; GFAP, glial fibrillary acidic protein; NeuN, neuronal nuclei.

Figure 2. Proposed pathways for extra- and intracellular formation of Ang II in neurons

In presympathetic neurons, prorenin (PR) binds intracellular PRRs, stimulating the intracellular formation of Ang II, which is subsequently secreted into the extracellular space. Alternatively, extracellular prorenin binds to PRRs on the neuronal membrane and metabolizes extracellular AGT secreted by astrocytes or neurons to generate Ang I. ACE, located on the external surface of cell membranes or in the interstitial uid, converts Ang I to Ang II. Intracellular Ang II can be transported to axon terminals to act as a neurotransmitter. Extracellular Ang II binds to AT₁R to modulate neuronal activity and neurotransmitter release at the synapse. Abbreviations: PR, prorenin; PRR, (pro)renin receptor; AGT, angiotensinogen; Ang II, angiotensin II; ACE, angiotensin converting enzyme; AT₁R, angiotensin II type 1 receptor; PVN, paraventricular nucleus of the hypothalamus; RVLM, rostral ventrolateral medulla nucleus. (Modified from Li W et al., Hypertension, 2013, 65:352–361.)

Figure 3. Antihypertensive drugs targeting the RAS

Schematic illustration of clinically approved antihypertensive agents that inhibit the RAS. Potential new RAS antagonists targeting the PRR (red square): HRP and PRO20 have been tested in vitro or in animals. Abbreviations: AGT, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; ACE, angiotensin converting enzyme; AT₁R, angiotensin II type 1 receptor; BP, blood pressure; HRP, handle region peptide.

Figure 4. Proposed mechanism for PRO20 blockade of prorenin/PRR activation as a therapeutic strategy

The PRR mediates prorenin (ligand)-dependent signaling by promoting Ang II formation or Ang II-independent downstream signals. Activation of these prorenin-dependent signaling pathways is responsible for cell proliferation, hypertension, and diabetic end-organ damage. The PRR also plays important roles in Wnt signaling pathways and autophagy that do not require prorenin. The latter signaling pathways are important for cell survival, embryonic development, and urine acidification. According, we propose that blocking the binding of prorenin to the PRR will prevent prorenin/PRR activation and Ang II formation, thereby preventing activation of downstream signaling. In addition, blocking activation of prorenin/PRR will not affect the prorenin-independent roles of the PRR in cell survival, embryonic development, or urine acidification. Abbreviations: AGT, angiotensinogen; Ang I, angiotensin I; Ang II, angiotensin II; ACE, angiotensin-converting enzyme; AT₁R, angiotensin II type 1 receptor; PLZF, promyelocytic zinc finger; MAPKs, mitogen-activated protein kinases; ERK1/2, extracellular signal-regulated kinases 1 and 2; PAI-1, plasminogen activator inhibitor-1; COX2, cyclooxygenase 2; NOX4, NADPH oxidase 4; LPR6, low-density lipoprotein receptor-related protein 6.

Figure 5. A global view of antihypertensive drug development

(A) Approved anti-hypertensive drugs with a single ingredient or multiple ingredients. (B) Antihypertensive drugs in development. Abbreviations: AR, adrenergic receptor; CC, calcium channel; HMGR, HMG CoA reductase; CM, calcium metabolism; MLR, mineralcorticoid receptor; NCC, Na/Cl transporter; NKCC2, Na-K-Cl cotransporter 2; NPR, natriuretic peptide receptor; nAChR, nicotinic acetylcholine receptor; OR, opioid receptor; PDE5, phosphodiesterase 5; VIPR, vasoactive intestinal peptide receptor.