(Pro)renin receptor, also known as ATP6AP2, is a single-pass transmembrane protein composed of 350 amino acids. It consists of an N-terminal extracellular domain composed of a hydrophobic region (amino acids 1-16), a transmembrane domain and a short cytoplasmic domain (3, 10). The gene that codes PRR is located on the X chromosome (Xp11.4). Full-length PRR expression was found to be higher in thyroid, brain, kidney, adrenal, endometrium, heart, appendix and 18 other tissues and lower in pancreas and salivary gland (11), and it is mainly present on endomembrane systems, including vacuolar membranes and plasma membranes (10).

As PRR was first reported, it was found to facilitate AGT cleavage and increase angiotensin (Ang) II production and function (3, 12). The binding of (pro)renin to the PRR triggers a conformational change and non-proteolytic activation of (pro)renin, resulting in Ang I being derived from AGT (Figure 1A). ACE further converts Ang I to Ang II. This discovery may explain the issue of how the low level of renin maintains a high level of Ang II activity in the brain (13) and make PRR a new member of the RAS system. It was clear that the effect of PRR enhancing the generation and action of Ang II in the brain plays a role in neurogenic hypertension (4, 14). However, compared with the Ang II-dependent pathway of PRR, the intracellular signaling molecules activated by PRR independent of Ang II might be more important in inflammation and fibrosis of the myocardium, kidney, and other tissues in pathologic conditions and have received more attention. When binding with (pro)renin, PRR directly activates the downstream intracellular signaling pathways, including the extracellular signal-related protein kinase (ERK) 1/ERK2 pathway, p38 mitogen-activated protein kinases (p38MAPKs)–heat shock protein (HSP) 27 pathway and phosphatidylinositol 3-kinase–p85α (PI3K-p85α) pathway, independent of Ang II (15–17) (Figure 1B). This process triggers a sequence of cascade reactions and ultimately upregulates a series of nuclear factors, which are important contributors to tissue injury and fibrosis in disease (18–20, 21). However, some researchers overexpressed PRR in normal mice, no increase in blood pressure and no tissue damage were observed (22). This might indicate that PRR is not a primary initiator of tissue damage but exacerbates tissue injury in pathological conditions (22).

A truncated form of PRR named M8.9 was found to be an accessory protein of vacuolar H + -ATPase (V-ATPase) and plays a critical role in V-ATPase biogenesis (23, 24) (Figure 1D). Previous studies showed that abnormal cytoskeleton and impaired autophagy caused by the deletion of PRR significantly affected cell survival (23, 25). These studies might suggest that the deletion of PRR is more lethal than the overexpression of PRR. Although it is still controversial whether moderate knockdown of PRR under pathological conditions will lead to lysosomal dysfunction and autophagy impaired, apparently the best option would be to block PRR without affecting M8.9, and not knockdown gene expression.

Interestingly, Cruciat et al. (26) found that PRR is an important component of the Wnt receptor complex together with Frizzled, V-ATPase and a low-density lipoprotein receptor-associated protein 6 (LRP6) and participates in the activation of Wnt/β-catenin signaling, which contributes to cell development and may participate in tissue fibrosis (Figure 1C). This discovery provides another possible mechanism for the physiological and pathological effects of PRR.

In addition to M8.9, in 2009, a 28-kDa soluble (pro)renin receptor (sPRR) was found in plasma (27). These findings might indicate that the full-length PRR is cleaved by some means. However, the generation of sPRR remains controversial. Cousin et al. (27) reported that PRR was cleaved by furin in the trans-Golgi, which generates a 28-kDa sPRR and an additional 10-kDa fragment. However, there is no evidence that the 10-kDa fragment is M8-9, the accessory protein of V-ATPase. In contrast, another study found that metalloproteinase ADAM19 mediates the shedding and cleavage of PRR in Golgi and generates 29 kDa NTF-PRR and CTF-PRR (28), which may suggest furin is not the only cleavage protein of full-length PRR. Recently, Nakagawa et al. (29) found that the cut site of sPRR fits well to the cleavage site of Site-1 protease (S1P), a member of the subtilisin-like proprotein convertase family. Through the use of specific S1P knockdown, they proposed that full-length PRR was first cleaved by S1P and further cleaved by furin to generate sPRR, which was secreted extracellularly (29). Furthermore, an animal experiment confirmed that inhibition of S1P effectively reduced the sPRR level in Ang II–induced hypertension mice (30), which may suggest that S1P is the rate-limiting protein in the production of sPRR. Multiple clinical studies have confirmed the relevance of sPRR and some diseases, including gestational diabetes (31), essential hypertension (32), chronic heart failure (33), and renal damage (34); however, the physiological function and pathological mechanism of sPRR have not been elucidated to date.

In physiological state, PRR was discovered high expression in human brain, heart, kidney and colon (11). There are sufficient evidences suggested that PRR plays an important role in cell proliferation and cell cycle progression (35–37). This effect might be associated with Wnt/β-catenin (35). There are numerous literature reports on the essential role of Wnt/β-catenin in cell survival and proliferation, cell fate and movement (38). As part of Wnt receptor complex, PRR knockdown impairs cell proliferation and normal morphogenesis both through canonical and non-canonical Wnt/PCP signaling pathway, which leads to neurodevelopmental abnormalities in mice (35). Wanka et al. also demonstrated that PRR knockdown decreases cell proliferation and a cell cycle arrest in the G0/G1 phase in renal As4.1 cells (36). Moreover, another study showed that PRR overexpression facilitates cell proliferation in hippocampal neural stem cells (37). This finding provides further evidence of the above research.

As mentioned above, the truncated form of PRR is an important accessory protein of V-ATPase. V-ATPases are proton-pumping membrane proteins that drive protons into the lumen of lysosomes using ATP hydrolysis’ free energy (39). It contributes to maintaining the acidic environment of lysosome, and provides a conducive environment for lysosomal hydrolase activity (39). Kinouchi et al. confirmed PRR ablation decreases the expression of V0 subunits of V-ATPase and caused V-ATPase function impairment (23). Their further study demonstrated that full-length PRR participants in V-ATPase biogenesis. M8.9 might be just a residue after cleavage of full-length PRR (24). Therefore, PRR is important in maintaining normal function of lysosome in physiological state. Deletion of PRR results in lysosomal acidification disorder and impaired autophagy, and finally leads to cell death (25).

(Pro)renin receptor was first been found as a new member of RAS. Existing studies demonstrate that PRR is involved in local RAS both through Ang II-dependent and -independent ways. However, whether PRR can mediate tissue inflammation and fibrosis by local RAS under physiological conditions remains controversial. Moilanen et al. overexpressed PRR by adenovirus in normal rat hearts and observed cardiac hypertrophy, extracellular matrix fibrosis and reduced cardiac ejection fraction, accompanied by activation of the ERK1/2 and p38MAPK-HSP27 pathways (40). They also suggested that PRR stimulated the p38 MAPK-HSP27 pathway at least partially through Ang II (40). Another research found that specific overexpression of PRR in normal mice hearts caused atrial fibrillation and cardiac remodeling via ERK1/2 (41). In contrast to these studies, some studies overexpressed PRR in the heart and were unable to notice myocardial injury or cardiac fibrosis (22). They proposed that PRR may aggravate tissue damage caused by inflammation or diabetes, but not to be the primary initiator (22). Batenburg et al. demonstrated that only overexpression (pro)renin but not PRR can stimulated intracellular signaling pathway (42). They also suggested that the low (pro)renin level in normal tissue was not enough to activate PRR (42). Moilanen et al. overexpressed PRR by recombinant adenoviruses that carry rat PRR genes (40). Comparatively, Rosendahl et al. constructed PRR gene overexpression mice to up-regulate PRR expression (22). Different methods and times of PRR overexpression may be responsible for the discrepant results. But this still lacks evidence and needs further research.

Altogether, under physiological states, in contrast to the controversial results of tissue damage and fibrosis caused by PRR, its importance for maintaining cell survival cannot be disputed. Therefore, downregulation of PRR gene expression is dangerous. Clinical treatment targeting PRR should focus on its blockers.

Since the PRR was first reported (3), considerable research has revealed the association between PRR and hypertension. PRR participates in the pathogenesis of hypertension as part of local RAS rather than system RAS. Therefore, PRR is involved in hypertension through different mechanisms in different tissues.

Myocardial ischemia reperfusion injury (MIRI) often occurs after myocardial infarction reperfusion therapy and causes further injury. Liu et al. (85) treated cardiomyocyte cells (H9C2) with 2h of hypoxia followed by 6 h of reoxygenation to mimic ischemic-reperfusion injury in vitro and found that PRR expression was upregulated. PRR small interfering RNA reduced p38-MAPK activation and decreased hypoxia/reoxygenation-induced apoptosis via p38-MAPK (85). Furthermore, some researchers demonstrated that PRR overexpression increased apoptosis and autophagy in H9C2 cells treated with hypoxia/reoxygenation condition (86). They first proposed that this effect may occur through the Wnt/β-certain pathway because a Wnt inhibitor (DKK-1, 20 ng/ml) reversed the above effects (86), though this result has not been validated in vivo.

Metabolic cardiomyopathy is a type of secondary cardiomyopathy, often secondary to basal metabolic diseases, including diabetes, obesity and alcohol intake (94). Diabetes is the most common disease of these patients. Our previous study demonstrated that PRR RNA interference silencing attenuated the inflammatory response, cardiomyocyte apoptosis and myocardial fibrosis in (DCM) (5, 95), which can be associated with lower NOX4 expression (95). NADPH oxidase (NOX4) not only increases ROS production but also mediates fibroblast proliferation and might further activate ERK1/2 and p38 MAPK (96), which may be an important mechanism by which PRR causes cardiac fibrosis. We also showed that PRR upregulated inflammatory factor expression, induced cardiomyocyte apoptosis and myocardial fibrosis, and promoted ROS production (5). These effects can be reversed by an ERK inhibitor in fibroblasts stimulated by high glucose (5). In addition to DCM, our study also showed that a similar effects of PRR in alcoholic cardiomyopathy model rat, which was that PRR promoted myocardial fibrosis in alcoholic cardiomyopathy (ACM) rats via PRR-ERK-NOX4 (6) (Figure 2). These in vivo and in vitro studies imply that PRR might be a new therapeutic target in metabolic cardiomyopathy.

Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a crucial enzyme in regulating energy metabolism homeostasis and stress, and it contributes to pathogenesis of type 2 diabetes (97). Recent research suggested that in diabetes, PRR can decrease AMPK phosphorylation, which might mediate mitochondrial biogenesis and result in function impairment (98). Our previous study verified that PRR reduced AMPK phosphorylation in DCM (99). Our recent research also found that PRR mediated cardiac inflammation and fibrosis in DCM, at least partly through enhancing yes-associated protein (YAP) expression (100). YAP is a key protein that mediates mechanical signaling and cell proliferation (101) and promotes the transcription of downstream target genes through nuclear translocation. Phosphorylation of YAP causes its cytoplasmic localization, which prevents YAP nuclear translocation and further decreases target gene activation (101). Recent studies found that YAP promoted fibroblast differentiation and activation and increased extracellular matrix fibrosis (102). Tissue fibrosis was attenuated by selective knockout of YAP expression (102). Our studies illustrated PRR overexpression increased YAP expression, and a YAP inhibitor could reverse PRR-mediated cardiac fibrosis (99). Furthermore, the PRR-induced increase in YAP expression might occur partly through the downregulation of AMPK phosphorylation (99, 100). In our experiments, we have not clarified whether PRR regulates YAP phosphorylation and nuclear translocation. However, studies have elucidated that AMPK promotes YAP phosphorylation and prevents its nuclear translocation (103). PRR may also increases YAP nuclear translocation through down-regulation of AMPK in DCM. Moreover, Yoshida et al. (104) showed the association of PRR and YAP, presumably through the activation of the Wnt/β-certain pathway. YAP was regarded as a downstream effector of Wnt/β-certain (105) (Figure 2). Further research is needed to find out the relationship among PRR, Wnt/β-certain and YAP pathway, and their roles in cardiac remodeling.

Atherosclerosis is the most common vascular disease characterized by arterial wall thickening and atherosclerotic plaque or lesion formation and results in coronary heart disease (CAD), cerebral infarction, myocardial infarction and multiple diseases (106). In the pathogenesis of atherosclerosis, lipid metabolism disorder is the pathological basis of atherosclerosis. Lipid deposition and lipid-phagocytosed macrophage accumulation play vital roles in the formation of arterial plaques (107, 108). There is compelling clinical evidence that dyslipidemia is significantly associated with the risk of atherosclerosis. In particular, low-density lipoprotein (LDL), as the cholesterol carrier protein, is an independent factor for predicting the risk of cardiovascular disease (108, 109). Interestingly, the present study found that PRR was a new component of the lipid metabolism pathway (110), which suggests that PRR might participate in atherosclerosis in this manner (111).

Lu et al. (110) confirmed sortilin (SORT) 1, a recently identified key regulatory protein of LDL metabolism, as a PRR-interacting partner through an unbiased proteomics approach. They demonstrated that PRR gene silencing decreased SORT 1 abundance but without significantly reducing the mRNA expression of SORT 1, and PRR gene silencing also decreased LDL receptor abundance, which impaired LDL uptake (110). These effects might be related to PRR depletion mediating V-ATPase dysfunction and lysosome impairment because the LDLR abundance reduction could be partly rescued by lysosomotropic agents (110). Strong et al. (111) suggested that PRR advances SORT1 and LDLR transport to the cell surface, and SORT1 protects LDLR from degeneration by lysosomes. This hypothesis provides a possible model for the interaction of PRR, SORT1 and LDLR. However, unexpectedly, in the current research (112), PRR gene silencing even reduced plasma low-density lipoprotein cholesterol (LDL-C) and triglycerides. They elucidated that this effect might be due to PRR inhibition reducing the abundance of acetyl-CoA carboxylase (ACC) and pyruvate dehydrogenase (PDH) in hepatocytes, resulting in reduced lipid synthesis (112). As a consequence, hepatic PRR inhibition improved diet-induced obesity and liver steatosis (112). Interestingly, Gatineau et al. (113) showed that liver PRR knockout might compensate for elevated sPRR cleavage and secretion from adipose tissue, which increased sterol regulatory element-binding protein 2 (SREBP2) expression and hepatic cholesterol synthesis. Taken together, hepatic PRR and sPRR both contribute to lipid synthesis and LDL uptake in intricate ways, which affect plasma LDL levels and may cause atherosclerosis and CAD.

In addition to lipid synthesis and metabolism, migration and proliferation of vascular smooth muscle cells (VSMCs) are also key events in atherosclerosis and vascular remodeling. Previous studies have shown that (pro)renin combines with PRR in smooth muscle cells, which contributes to the migration and proliferation of VSMCs by regulating plasminogen activator inhibitor-1 (PAI-1) expression (114, 115). Further studies confirmed (pro)renin as a potential chemotactic factor. When combined with PRR, it activates RhoA-GTP and Rac1-GTP and promotes the cleavage of focal adhesion kinase (pp125FAK), which causes cytoskeleton reorganization and VSMC migration (116). Some studies questioned the significance of these conclusions because the (pro)renin level of vascular smooth muscle did not reach the concentration that activated PRR (42). However, in our recent study, we still found that overexpressed PRR facilitated the formation of Ang II-induced abdominal aortic aneurysm in apolipoprotein E-knockout mice (7). These conflicting conclusions might be because PRR is not only activated by (pro)renin or renin but can also be directly activated by Ang II or others. This conjecture has received indirect support from some research, but it still needs further verification.