Is natriuretic peptide receptor C a new target for hypertension therapeutics?

Natriuretic peptides (NPs) include atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). NPs exert cardiovascular protective effects through interaction with their receptors. There are two major classes of NP receptors: guanylyl cyclase-coupled receptors A and B (NPR-A and NPR-B) and inhibitory guanine nucleotide regulatory protein (Gi)-coupled receptor C (NPR-C, Fig 1). The cardiovascular protective effects of NPs have been primarily attributed to elevation of intracellular cGMP via NPR-A and NPR-B¹. NPR-C, initially indentified as a clearance receptor ², has been shown to inhibit adenylyl cyclase via the α subunit of the inhibitory G-proteins (Giα) and stimulate phospholipase C signaling via the βγ subunits of the same Gi protein³. NPR-C is widely distributed in many tissues and cell types, and has higher density than NPR-A and NPR-B in most tissues⁴. Ligands for NPR-C include ANP, BNP, CNP and C-ANP_4-23. C-ANP_4-23, a ring deleted analog of ANP, is a specific and selective NPR-C agonist (Fig 1). Multitudes of studies have underscored the importance of NPs and NPR-C in regulating cardiovascular homeostasis and have proposed NPs and NP receptors as potential targets for therapy for cardiovascular diseases.

Figure 1. NPR-C, its downstream signaling and potential pharmaceutical formulations of C-ANP_4-23 for the hypertension therapeutics.

C-ANP_4-23 treatment induces anti-hypertensive effects by reducing oxidative stress and restoring vasorelaxation. C-ANP_4-23 could also inhibit clearance of NPs from circulation accentuating its anti-hypertensive effects. Bioencapsulation and nanotechnology can be used to effectively deliver this physiologically active peptide orally to increase patient compliance and therapeutic efficacy, and reduce cost. NPs: natriuretic peptides; NPR-C: natriuretic peptide receptor C; PLC: phospholipase C; Gi: inhibitory guanine nucleotide regulatory protein.

Both genetic and pharmacological evidence have implicated the involvement of NPs and NPR-C in hypertension. For example, polymorphisms in NPR-C gene appear to be associated with hypertension⁵. In addition, administration of BNP decreases blood pressure in both animal hypertension models and humans^6,7. It is in this context that the study of Li et al. in this issue of Hypertension is relevant. Li’s group has demonstrated that intra-peritoneal injection of C-ANP_4-23 decreases levels of Giα and oxidative stress and also prevents the increase in blood pressure in pre-hypertensive spontaneously hypertensive rats (SHR, Fig 1). In addition, it attenuates high blood pressure in adult SHR and restores vasorelaxation toward control levels. This is the first indication that NPR-C agonist could be considered as a therapeutic target for hypertension and related pathophysiology. However, significant issues must be addressed in order to move this concept forward such as follows:

Firstly, prevention studies are relevant but have limited clinical significance in view of the lack of reliable marker(s) for hypertension/cardiovascular diseases. Thus, long-term reversal studies and their validation, with the use of multiple animal models of hypertension, would be extremely valuable. Secondly, NPR-C also acts as a clearance receptor for NPs. Thus, it is relevant to determine the chronic effects of C-ANP_4-23 treatment on overall health and physiology of the animal given the observation that genetic changes in NPR-C result in abnormalities. In addition, C-ANP_4-23 could increase ANP levels which may lead to unwanted pathophysiological consequences. Thirdly, development of proteins/peptides as therapeutic agents is challenging as a result of tremendous technical and financial restrictions, not to mention significant compliance issues. Innovative nanoparticles⁸ and plant-based technologies⁹ are now available to encapsulate therapeutic peptides for oral delivery (Fig1). Adapting any of these techniques to deliver C-ANP_4-23 orally would be the logical next step in providing conceptual support for the therapeutic potential of this peptide.

In summary, activation of the NPR-C signaling pathway represents a new therapeutic opportunity to refine and improve existing therapies to achieve target-organ protection, blood pressure control and optimal volume homeostasis.

This is a commentary on article Li Y, Sarkar O, Brochu M, Anand-Srivastava MB. Natriuretic Peptide receptor-C attenuates hypertension in spontaneously hypertensive rats: role of nitroxidative stress and gi proteins. Hypertension. 2014;63(4):846-55.