The Prorenin Receptor: Multitasking Its Way Through Cardiovascular, Metabolic, and Renal Diseases

1. Introduction

The renin–angiotensin–aldosterone system (RAAS) is a key regulator of blood pressure (BP) and extracellular fluid homeostasis [1]. When inappropriately activated, however, RAAS signaling contributes to the development and progression of cardiovascular disease (CVD) and chronic kidney disease (CKD), including hypertension, diabetes mellitus, and metabolic disorders. The cloning of the receptor for renin and prorenin—now known as the prorenin receptor (PRR)—more than twenty-five years ago [2] has stimulated fundamental investigations regarding its role in CV and renal physiology and its contribution to systemic and tissue RAAS-mediated pathophysiological processes.

The PRR is widely expressed in several tissues in humans and rodents, including the heart, brain, placenta, kidney, vasculature, and adipose tissues, to name a few [2,3,4]. The PRR critically regulates CV function through both Angiotensin II (Ang II)–dependent and –independent mechanisms. In the kidney, PRR is highly expressed along the nephron, where it influences intrarenal RAAS activity and the handling of water and sodium [5,6]. Through these actions, it contributes to the regulation of BP, acid-base homeostasis, and remodeling processes [7].

Emerging clinical evidence suggests that the circulating form of the soluble PRR (sPRR) plays a role in CV, renal, and metabolic disorders. Elevated plasma sPRR levels have been reported in patients with type 2 diabetes, hypertension, and CKD, and correlate with markers of renal dysfunction and CV risk [8,9]. The sPRR may influence hepatic glucose production, adipose tissue inflammation, and systemic RAAS activity, thereby linking PRR signaling to broader metabolic disturbances [9]. In this review, we provide an update of the contributions of PRR in CVD, vascular development, metabolic diseases, and renal inflammation.

2. Prorenin Receptor in Cardiovascular, Metabolic and Renal Diseases

The PRR, also known as Atp6ap2, is a multifunctional receptor linking the RAAS with intracellular signaling pathways that regulate inflammation, fibrosis, and metabolic homeostasis [10]. PRR was initially identified as a receptor that binds both prorenin and renin, with its role dependent on their activity/activation. Further studies found that PRR enhances catalytic conversion of angiotensinogen to Angiotensin I (Ang I), leading to increased local formation of Ang II in tissues fully independent of circulating renin activity [10]. In addition to this enzymatic amplification of tissue RAAS, PRR activation triggers Ang II-independent intracellular signaling cascades, including activation of ERK1/2, p38 MAPK, and PI3K/Akt pathways. These signaling events stimulate transcription of profibrotic mediators such as transforming growth factor-β (TGF-β), plasminogen activator inhibitor-1 (PAI-1), and extracellular matrix proteins, implicating PRR in tissue remodeling and fibrosis [10,11].

Beyond its role in RAAS signaling, PRR functions as an accessory protein of the vacuolar H⁺-ATPase (V-ATPase), which is essential for intracellular acidification, vesicular trafficking, and autophagy [3]. Through this interaction, PRR regulates lysosomal function and cellular metabolism. Disruption of the PRR–V-ATPase pathway impairs intracellular pH and protein degradation—processes increasingly recognized as key contributors to metabolic dysfunction and cellular stress [13]. These findings highlight PRR as a molecular hub integrating extracellular hormonal signals with intracellular metabolic pathways. In cardiomyocytes, PRR is closely associated with the V-ATPase and the ryanodine receptor, positioning it at the interface of intracellular calcium handling, lysosomal function, and downstream signaling pathways that influence myocardial contractility and structural integrity [13].

Cardiac PRR expression is upregulated in pathological states including diabetes, myocardial infarction, and heart failure, supporting its involvement in maladaptive cardiac remodeling [10,14]. Both low and high sodium diets increase myocardial prorenin/renin and PRR expression, leading to enhanced fibrotic remodeling under conditions of extreme sodium imbalance [15,16]. Despite these associations, the role of cardiac PRR in systemic BP regulation remains unclear. Constitutive deletion of PRR in cardiomyocytes results in lethal heart failure due to impaired lysosomal acidification, underscoring its essential role in cardiomyocyte homeostasis [13]. In contrast, global or cardiomyocyte-specific PRR overexpression does not significantly alter baseline BP or cardiac morphology. Adenovirus-mediated PRR overexpression in adult rat hearts induces Ang II–independent activation of intracellular signaling pathways and reduces left ventricular ejection fraction, indicating that PRR can directly promote cardiac dysfunction independent of systemic RAAS activation [17]. These findings suggest that cardiac PRR critically regulates myocardial remodeling and function rather than exerting a dominant influence on hemodynamic control.

In vascular smooth muscle cells (VSMCs), PRR expressed at the cell surface plays a more direct role in BP regulation and vascular remodeling [2,18]. VSMC-specific human PRR overexpression in transgenic rats induces hypertension and tachycardia, whereas PRR deficiency in VSMCs leads to aortic sclerosis without significant changes in BP, highlighting its context-dependent actions within the vasculature. PRR activation in VSMCs stimulates cellular proliferation, ERK1/2 signaling, and the expression of inflammatory and profibrotic mediators, including PAI-1, reinforcing its contribution to vascular injury and remodeling [18]. Collectively, these data indicate that while cardiac PRR predominantly influences myocardial structure and function, vascular PRR plays a more prominent role in the regulation of BP and the progression of vascular pathology, positioning PRR as a key molecular link between hemodynamic stress and CV remodeling.

In the kidney, PRR is abundantly expressed in collecting duct intercalated cells, podocytes, and mesangial cells, where it contributes to both renal sodium handling and glomerular integrity [19,20]. The PRR plays a critical role in nephrogenesis, as its deletion in nephron progenitor cells results in reduced nephron number, podocyte abnormalities, and proteinuria [21]. The PRR is thought to regulate kidney development partly through Wnt/β-catenin signaling, which coordinates ureteric bud branching and nephron formation. In the mature kidney, PRR contributes to the regulation of water and sodium homeostasis. PRR activation increases intrarenal RAAS and epithelial sodium channel (ENaC) activity, promoting sodium retention and the development of hypertension [4,19,22]. In models of diabetic nephropathy, PRR expression is markedly upregulated in glomerular cells, where it stimulates oxidative stress, extracellular matrix accumulation, and inflammatory signaling [10]. These findings, along with evidence that PRR activates Wnt/β-catenin signaling, highlight its critical role in driving renal fibrosis and promoting epithelial-mesenchymal transition during the progression of CKD.

2.1. Prorenin Receptor Signaling in Metabolic Homeostasis and Disease

The PRR in adipose tissue modulates biology and obesity-associated metabolic alterations. PRR expression is increased in adipose tissue under metabolic stress, including high-fat diet–induced obesity. PRR activation promotes adipocyte hypertrophy, inflammatory cytokine production, and oxidative stress, thereby contributing to adipose tissue dysfunction and systemic insulin resistance [23,24]. In addition, PRR has been implicated in the regulation of adipocyte metabolism through its association with the V-ATPase complex and Wnt/β-catenin signaling-pathways that are critical for adipocyte differentiation and energy homeostasis [23,25].

Growing evidence indicates that the soluble form of prorenin receptor (sPRR), generated by proteolytic cleavage of the membrane-bound receptor, is a circulating factor potentially involved in metabolic diseases. Elevated circulating levels of sPRR are present in patients with obesity, type 2 diabetes, and metabolic syndrome, suggesting that this form may serve as a potential biomarker or mediator of metabolic dysfunction [8]. The sPRR also influences glucose metabolism, adipose tissue inflammation, and insulin signaling, linking PRR activity to systemic metabolic regulation [23,26,27]. Collectively, these findings support the concept that PRR functions as an important molecular integrator connecting RAAS, cellular metabolism, and inflammatory pathways, thereby contributing to the development and progression of metabolic disorders.

2.2. Prorenin Receptor as a Regulator of Endothelial Signaling, Angiogenesis, and Vascular Remodeling

The PRR is a key modulator in developmental angiogenesis. Endothelial cell–specific deletion of PRR in mice leads to severe defects in retinal vascular development characterized by impaired endothelial cell migration, loss of tip cell polarity, and defective sprouting angiogenesis [28]. These abnormalities reflect dysregulation of genes governing cell migration, polarity, extracellular matrix organization, and angiogenic signaling, and indicate that PRR is critical for proper vascular network formation.

In addition to its role in endothelial signaling and angiogenesis, the Atp6ap2 gene has been increasingly recognized as an important contributor to vascular remodeling, a key pathological process underlying hypertension and CVD. Independent from Ang II, the activation of PRR by renin or prorenin initiates intracellular signaling pathways—including ERK1/2–MAPK, PI3K/Akt, and Wnt/β-catenin—that regulate VSMC proliferation, migration, and extracellular matrix production. [2,28,29]. These processes promote structural changes within the vascular wall, including media thickening, increased collagen deposition, and reduced vascular compliance, which contribute to elevated peripheral resistance and sustained hypertension.

During oxidative stress, the PRR mediates vascular injury by driving maladaptive vascular remodeling. PRR signaling can enhance the production of reactive oxygen species (ROS) through activation of NADPH oxidase pathways, leading to endothelial dysfunction and vascular inflammation [27,30]. These processes facilitate leukocyte recruitment, extracellular matrix reorganization, and vascular wall hypertrophy. PRR-associated signaling through V-ATPase and Wnt/β-catenin pathways may regulate gene programs involved in vascular cell growth and tissue remodeling, linking PRR to both developmental vascular patterning and pathological vascular remodeling in adult tissues [25,28]. These findings position PRR as a central molecular regulator of vascular remodeling, integrating RAAS-dependent and independent signaling that contribute to the structural and functional changes in hypertension and other CVD. Collectively, we propose that PRR functions as a molecular hub that integrates metabolic, developmental, and signaling pathways to regulate endothelial cell behavior, angiogenic remodeling, and vascular development.

2.3. Prorenin Receptor Pathogenic Feedback Loops and Chronic Kidney Disease

In addition to classical renin production by juxtaglomerular cells, renin and its precursor prorenin are synthesized by the distal nephron segments [6]. Prorenin produced by the collecting duct is regulated by hormones acting on the distal nephron rather than by BP [6,31]. Binding of PRR to renin and prorenin increases local renin enzymatic activity, activates prorenin, and augments intratubular Ang II formation. Increased distal prorenin production and secretion into the lumen has been demonstrated in several experimental hypertensive animal models, including chronic Ang II–infusion, 2-kidney 1-clip (2K1C) Goldblatt hypertension, and transgenic mice with renin deficiency in the collecting duct [6,19,31,32]. Likewise, these findings are present in mice with high fat diet-induced type II diabetes and rats with streptozotocin-induced type 1 diabetes [7,33].

The PRR activation by its natural agonists, renin and prorenin, promotes kidney fibrosis and inflammation through various pathways independent of the RAAS [6,10]. Its activation directly triggers intracellular signal transduction via ERK1/2 and upregulation of profibrotic genes, including TGF-β1, fibronectin, collagen I, and PAI-1 [7,34,35]. Likewise, PRR exerts a positive feedback action on the Wnt/β-catenin signaling, which exacerbates renal fibrosis and inflammation in hypertensive nephropathy [36]. This crosstalk establishes a feed-forward loop that sustains inflammatory and profibrotic signaling over time and accelerates maladaptive tissue remodeling. Consistent with this pathogenic role, experimental inhibition or knockdown of PRR in ischemia–reperfusion kidney injury models significantly attenuates renal fibrosis and further support its role as the key amplifier of fibrosis [10].

The PRR has gained significant attention as a potential therapeutic target for CV and renal diseases. The handle region peptide (HRP) was the first PRR-blocking peptide identified; however, its specificity in inhibiting PRR signaling has been widely debated [37]. In contrast, the PRR decoy inhibitor PRO20—composed of the first 20 amino acids of the prorenin pro-segment—has produced more consistent and less controversial results. Its efficacy has been validated in multiple rodent models of hypertension, fluid, and electrolyte imbalances [30,38,39,40,41]. These studies indicate that PRO20 disrupts the interaction between the pro-segment of prorenin and PRR without altering PRR expression, thus reducing inflammation and injury in models of Ang II-dependent hypertension and diabetic nephropathy.

2.4. Prorenin Receptor Contributes to Systemic and Renal Inflammation

Pathologic upregulation of PRR is strongly associated with enhanced renal and systemic inflammation in disease states including diabetes, hypertension, and renal ischemia. Increased PRR expression correlates with activation of ERK1/2 and p38 MAPK, as well as proinflammatory transcription factors such as NF-κB [35,40,42]. Activation of these pathways increases inflammatory mediators including TNF-α, IL-1β, MCP-1, and COX-2 [36,43], and promote immune cell recruitment and progressive renal injury independent of the RAAS. Although PRR overexpression in healthy animals does not independently induce hypertension or renal injury, it functions as a pathological amplifier to exacerbate inflammation and fibrosis under disease conditions [17]. In the 2K1C model of renovascular hypertension, PRR expression is selectively upregulated in the ischemic kidney, which is accompanied by marked increases in TNF-α, IL-1β, MCP-1, COX-2, phosphorylated NF-κB, and collagen type I, despite comparable elevations in intrarenal Ang II levels [10]. Furthermore, targeted intrarenal knockdown of PRR using shRNA significantly attenuates inflammatory cytokine expression, NF-κB activation, fibrosis, and albuminuria without altering BP or renal Ang II levels [35]. In addition, PRR inhibition can reduce inflammation and fibrosis in heart and liver disease models, supporting a broader role for PRR in systemic inflammatory signaling across organs [23,44].

3. The Soluble Prorenin Receptor: A Circulating Link Between the RAAS and Cardiorenal System

The discovery of the soluble form of the PRR (sPRR) has expanded the conceptual framework of PRR biology from a membrane-restricted receptor to a molecule capable of mediating local and systemic signaling effects. Functionally, sPRR retains the ability to bind prorenin and renin, thereby facilitating activation of the RAAS in extracellular compartments [6,45]. Beyond its role in RAAS activation, growing evidence also indicates that sPRR can directly modulate intracellular signaling pathways associated with inflammation, oxidative stress, and fibrosis [46,47]. The sPRR is produced by proteolytic cleavage of the full-length receptor by serine-proteases, including site-1 protease (SP-1), furin, and A Disintegrin And Metalloproteinase 19 (ADAM19) [26,45]. The released sPRR is detectable in plasma, cerebrospinal fluid, urine, and extracellular media [45,47]. It retains the ability to bind renin and prorenin, enhancing angiotensinogen conversion to Ang I and promoting downstream Ang II formation [47]. Although once thought to be just a by-product of receptor processing, growing evidence shows that sPRR is biologically active and has endocrine-like properties, enabling it to affect cellular signaling and systemic physiology.

In contrast to plasma renin activity, systemic sPRR levels may reflect circulating and tissue RAAS activation and indicate risk of CV and renal diseases. Increased circulating concentrations of sPRR have been found in individuals with hypertension, heart failure, and type 2 diabetes, correlating with indices of disease severity and target-organ damage [8,48]. Uremic toxins further potentiate PRR-dependent fibrosis. Indoxyl Sulfate (IS), a protein-bound uremic toxin that accumulates during CKD, upregulates PRR expression in mesangial cells and induces TGF-β, type IV collagen, and fibronectin expression via ERK1/2 activation. These effects are markedly suppressed by PRR knockdown [49]. IS also increases matrix metalloproteinase-9 (MMP9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression, promoting ECM remodeling and mesangial expansion [34]. Clinically, circulating sPRR levels correlate with serum IS and histopathological indices of mesangial injury in CKD, supporting the concept that sPRR is a potential biomarker of mesangial fibrosis [34]. The fact that sPRR can directly promote fibrotic and oxidative stress responses via PI3K-Akt/β-catenin and NOX4-dependent pathways further implicate PRR signaling as a pathogenic driver of chronic tissue fibrosis [42,50].

In the kidney, sPRR plays a key role in the regulation of sodium and water balance. The sPRR stimulates sodium reabsorption in the distal nephron, partly through activation of ENaC in collecting duct epithelial cells. By this mechanism, it contributes to enhanced sodium retention and to the development of hypertension [19,51]. Additionally, sPRR may amplify intrarenal RAAS activity, creating a positive feedback loop that sustains renal inflammation and fibrosis in CKD. Elevated plasma sPRR levels have been reported in patients with CKD and diabetic nephropathy, suggesting that sPRR may serve as both a mediator and a biomarker of renal injury [8,52,53].

In the vasculature, sPRR promotes endothelial dysfunction and vascular remodeling by enhancing oxidative stress and inflammatory signaling [52]. In metabolic tissues such as the liver and adipose tissue, sPRR may influence glucose metabolism and insulin sensitivity, potentially linking PRR signaling to broader met.abolic dysregulation [23].

From a clinical perspective, circulating sPRR has gained attention as a potential biomarker for cardiorenal disease progression. Measurement of plasma sPRR levels may provide insights into the activation of tissue RAAS and associated pathological processes, including fibrosis, inflammation, and sodium retention. Because sPRR reflects both PRR expression and proteolytic processing, it may serve as an integrative indicator of PRR pathway activation across multiple organs. Although sPRR is not currently adopted in the clinical practice, accumulating data supports its value to help identify patients at risk for CVD, progressive kidney disease, resistant hypertension, or adverse cardiovascular outcomes.

4. Conclusions

Over the past two decades, the PRR has been established as a multifunctional regulator that extends far beyond its functions within the RAAS. The PRR is an important molecular hub integrating RAAS-dependent and -independent signaling pathways, influencing diverse cellular processes including endothelial signaling, angiogenesis, vascular remodeling, metabolic regulation, and renal homeostasis. Through PRR-dependent activation of intracellular pathways such as ERK1/2-MAPK, PI3K/Akt, and Wnt/β-catenin, and its interaction with the V-ATPase complex; PRR regulates cellular proliferation, inflammation, oxidative stress, and fibrosis—key mechanisms underlying the pathogenesis of CV, metabolic, and renal diseases.

Emerging studies suggest that sPRR may act as a circulating mediator, linking tissue RAAS activity to systemic metabolic and cardiorenal dysfunction. The discovery of sPRR has significantly broadened the understanding of PRR biology. Rather than functioning solely as a membrane receptor, the PRR now appears to operate through both membrane-bound and soluble signaling mechanisms, allowing communication between organs such as the kidney, heart, vasculature, and metabolic tissues. New insights into PRR biology offer the potential for novel therapeutic interventions to treat cardiometabolic and cardiorenal diseases by targeting PRR-associated pathways. Further research will be necessary to clarify the tissue-specific functions of PRR and to determine how modulation of PRR/sPRR signaling can be translated into effective clinical strategies. Future studies into the regulation of sPRR generation, signaling mechanisms, and clinical associations will be crucial for determining whether targeting the PRR–sPRR axis may provide new diagnostic or therapeutic opportunities in CV, metabolic, and renal diseases