The role of (pro)renin receptor and its soluble form in cardiovascular diseases

Abstract

The renin-angiotensin system (RAS) is a major classic therapeutic target for cardiovascular diseases. In addition to the circulating RAS, local tissue RAS has been identified in various tissues and plays roles in tissue inflammation and tissue fibrosis. (Pro)renin receptor (PRR) was identified as a new member of RAS in 2002. Studies have demonstrated the effects of PRR and its soluble form in local tissue RAS. Moreover, as an important part of vacuolar H+-ATPase, it also contributes to normal lysosome function and cell survival. Evidently, PRR participates in the pathogenesis of cardiovascular diseases and may be a potential therapeutic target of cardiovascular diseases. This review focuses on the effects of PRR and its soluble form on the physiological state, hypertension, myocardial ischemia reperfusion injury, heart failure, metabolic cardiomyopathy, and atherosclerosis. We aimed to investigate the possibilities and challenges of PRR and its soluble form as a new therapeutic target in cardiovascular diseases.

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

“…In patients with acute decompensated heart failure and chronic heart failure, furin activity is increased due to myocardial stress, which contributes to the elevated levels of BNP to compensate for cardiac function . Consistently, several furin substrates have been shown to contribute to the pathogenesis of heart failure (Figure ), including inflammatory (TNF-α), remodeling/fibrosis (TGF-β1 and MMP2), and hypertrophic (soluble PRR-mediated AT II, BNP, and ET-1) factors, supporting the role of furin in this setting. ,,− …”

“…Notably, the current evidence suggests that soluble PRR also produces pathobiological functions, including sodium−water retention (via activation of epithelial sodium channel [ENaC]), hypertension (via the local renin−angiotensin−aldosterone system [RAAS]), and heart failure. 53,55 However, there are inconsistencies between preclinical and human data. Several animal studies have demonstrated the association between soluble PRR and hypertension.…”

“…PRR is a receptor for prorenin and renin, which is widely expressed (e.g., in the brain, heart, kidneys, adrenal gland, and pancreas). − Binding of prorenin/renin with membrane-bound PRR promotes hypertension, inflammation, tissue remodeling, and fibrosis − by activating prorenin (to active renin) and subsequent AT II generation, or by stimulating mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, which leads to upregulation of cyclooxygenase-2, TGF-β1, collagen, and fibronectin. − Soluble PRR is generated by furin, and it may localize inside the cells or be secreted. − Therefore, a reduction in furin levels may retain the intact membrane PRR to mediate pathological processes (Figure ). Notably, the current evidence suggests that soluble PRR also produces pathobiological functions, including sodium–water retention (via activation of epithelial sodium channel [ENaC]), hypertension (via the local renin–angiotensin–aldosterone system [RAAS]), and heart failure. , However, there are inconsistencies between preclinical and human data. Several animal studies have demonstrated the association between soluble PRR and hypertension. − In patients with essential hypertension, serum soluble PRR levels are not associated with blood pressure; rather, soluble PRR levels appear to reflect reduced renal function …”

The renin angiotensin aldosterone system

“…However, the following studies revealed that the expression of the PRR is not restricted to the kidney. Thus, PRR is present in the heart, testes, brain, placenta, thyroid and adrenal gland, and various cell types of the immune system [ 55 ]. The PRR has the following multifaceted functions: First, binding of renin to the receptor markedly increases its catalytical activity [ 38 ].…”

Assessment of the (Pro)renin Receptor Protein Expression in Organs

“…Because RAS has been elucidated as important in controlling vessel pressure/resistance and salt/water reabsorption of the kidney, evidence has also confirmed the pathogenic role of (P)RR in vascular and kidney-related diseases [ 1 , 3 , 4 ]. Moreover, it has been further suggested that the discovery of (P)RR might provide a plausible rationale for an issue about why a high Ang II activity could be caused by an extreme low expression level of renin in some tissues [ 5 , 6 ]. After two decades of study, (P)RR has been shown to widely express in many types of organs/tissues, e.g., vessel, heart, thyroid, brain, kidney, liver, colon, etc.…”