Natriuretic peptide system, biological effects
Natriuretic peptides are a family of structurally related hormonal factors. Atrial natriuretic peptide (ANP) and type B natriuretic peptide (BNP) are secreted by the atria and cardiac ventricles. Type C natriuretic peptide (CNP) is the most highly expressed natriuretic peptide in the brain, but is also highly expressed in chondrocytes and endothelial cells. Neutral neprilisin endopeptidase (NEP) is the enzyme that metabolizes natriuretic peptides. Natriuretic peptides mediate different physiological effects through interaction with specific guanylyl cyclase (GC) receptors that cause intracellular cGMP production. The main physiological effects are natriuresis / diuresis and peripheral vasodilation, inhibition of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) but other important biological functions have been highlighted in recent times. In particular, some studies have demonstrated an antifibrotic and anti-inflammatory action associated with natriuretic peptides. The natriuretic peptide type C (CNP), a member of the natriuretic peptide family, by selective binding to the transmembrane receptor guanylyl cyclase (GC)-B, mediates different biological effects in various organs. (37) CNP is expressed in a wide variety of tissues, such as the vascular endothelium, heart, bones and adrenal glands. (38) (39)(40)(41) CNP plays an important role in the regulation of local vascular tone, and has been shown to have mainly cardioprotective, antihypertrophic (42) and antifibrotic (43) effects. Recently, CNP has been shown to have protective effects against inflammatory and fibrotic reactions (44)(45). In vivo tests have revealed that CNP attenuates acute lipopolysaccharid-induced lung lesions (LPS) (46). CNP also regulates the secretion of inflammatory cytokines (47)(48).
In the inflammatory phase, expression levels of various chemokines, cytokines and growth factors are high and these mediators exert their profibrotic activity through the activation and proliferation of fibroblasts (49). Considering the pathophysiological importance of fibroblast activation in pulmonary fibrosis (50), and the above mentioned biological effects, it is suggested that there is a direct effect on pulmonary fibroblasts by natriuretic peptides. These insights suggest the use of therapeutic agents that increase the concentration of these peptides in the more severe stages of COVID-19 infection when a fibrotic pulmonary state is present. In association with evidence of antifibrotic and antihyperproliferative effects, the studies also show direct antiffiammatory effects mediated by the action of natriuretic peptides. In particular, some studies associate the BNP peptide with an important inhibitory effect on NALP3 inflammasome activation, which is related to BNP-induced downregulation of NF-kB and ERK1/2 activation. The data indicate a powerful anti-inflammatory and immunomodulatory role for this peptide. (51) These effects mediated by natriuretic peptides suggest an important role in COVID-19 infection.