The (pro)renin receptor (PRR) was originally cloned as a specific single-transmembrane receptor for prorenin and renin and has now emerged as a multifunctional protein implicated in a wide variety of developmental and physiopathological processes. Activation of PRR in the kidney causes Na+ and water retention, contributing to elevation of blood pressure in response to various hypertensive stimuli. Part of the renal action of PRR depends on activation of intrarenal renin-angiotensin system. In recent years, accumulating evidence suggests that the prohypertensive action of renal PRR was largely mediated by production of the 28-kDa soluble (pro)renin receptor through protease-mediated cleavage of the extracellular domain of PRR. The generation of multiple isoforms of PRR due to the protease-mediated cleavage partially explains diversified actions of PRR. The current review will summarize recent advances in understanding the roles of sPPR in animal models of hypertension.

© 2022 S. Karger AG, Basel

Introduction

(Pro)renin receptor (PRR), also known as ATP6AP2, is encoded by the gene ATP6AP2 on the X chromosome (locus p11.4) and composed of a transmembrane and cytoplasmic domain (termed M8.9), and a 28-kDa extracellular domain [1]. In vitro evidence demonstrates that PRR served as a specific receptor for prorenin and renin, with the potency to increase angiotensin (Ang) I-generating activity of renin and reversibly activating prorenin [1]. Prorenin or renin bound to PRR exhibits a three- to five-fold increase in renin activity [1]. Apart from renin-regulatory property, PRR is well known to be involved in activation of intracellular signaling transduction pathways such as mitogen-activated protein kinases (MAP) [1], phosphoinositide 3-kinase (PI3K)/AKT, wingless (WNT), oxidative stress, nuclear factor-κB (NFkB), and other pathways independent of AngII [2-7]. In agreement with the diverse properties, PRR plays pleiotropic actions in regulation of cell differentiation and proliferation, organ development, and tissue homeostasis dependent or independent of the renin-angiotensin system (RAS).

The expression and function of PRR in the kidney have been extensively investigated. Although PRR was originally discovered from mesangial cells [1], it is abundantly expressed in intercalated cells of the collecting duct (CD) with relatively lower expression in other nephron structures [8-10]. Majority of studies show that deletion of PRR in renal tubules [11] or the CD [12, 13] impairs urine-concentrating capability and attenuates hypertension development during AngII infusion. The prohypertensive role of PRR is dependent on activation of the intrarenal RAS and enhancement of α-epithelial Na+ channel (ENaC) expression [9, 14, 15]. Activation of PRR is also involved in various types of kidney diseases as evaluated using PRR decoy inhibitors such as handle region peptide [16] and PRO20 [17, 18].

PRR is cleaved by proteases to generate 28-kDa soluble (pro)renin receptor (sPRR), which is detectable in biological fluids by ELISA. Earlier studies showed that the cleavage process depended on furin or ADAM19 [19, 20]. However, recent studies by Nakagawa et al. [21] and us [22] using different approaches consistently demonstrated that site-1 protease (S1P) functioned as a predominant source of sPRR production. A large number of clinical studies examined the potential of sPRR as a disease biomarker. Elevated circulating sPRR has been associated with early pregnancy [23, 24], preeclampsia [25, 26], gestational diabetes mellitus [24, 27], renal dysfunction in patients with heart failure [28], obstructive sleep apnea syndrome [29-31], and chronic kidney disease (CKD) due to hypertension and type 2 diabetes [32]. In 2016, we for the first time discovered the biological function of sPRR in activation of transcription of aquaporin-2 and alleviation of polyuria in a mouse model of diabetic insipidus induced by antagonism of vasopressin type 2 receptor [10]. Subsequently, multiple studies from our group and others have defined the physiopathological roles of sPRR in various settings of Na+ and water balance, hypertension, and kidney disease [33-37]. In contrast, so far, no evidence is available to suggest a developmental role of sPRR. The main objective of this article is to review recent findings regarding the biological functions of sPRR in hypertension induced by AngII and obesity.

sPRR in AngII-Induced Hypertension

Both in vivo and in vitro evidence is available to suggest a potential role of renal PRR in mediating AngII-induced hypertension. In response to AngII infusion, renal PRR expression is elevated and further localized to the intercalated cells of the CD through COX-2/EP4 pathway [36, 38]. Specifically, during AngII infusion, COX-2-derived PGE2 via the EP4 subtype upregulates renal expression of PRR as well as local renin. AngII-induced hypertension was attenuated by conditional deletion of PRR in the CD associated with suppressed urinary renin level [39], supporting the intrinsic relationship between PRR and renin in the CD during AngII-induced hypertension. In agreement with this notion, CD-specific deletion of renin similarly attenuated AngII-induced hypertension [40], and conversely transgenic overexpression of renin in the CD elevated blood pressure (BP) [41].

Implication of sPRR in AngII-induced hypertension came from the original observation that urinary excretion of sPRR was augmented in AngII infusion in rats [14]. The recent identification of S1P as the predominant PRR cleavage enzyme permits assessment of the functional role of endogenous sPRR during AngII infusion. Subsequently, the effect of pharmacological inhibition of S1P by PF-429242 on AngII-induced hypertension was examined in F1 B6129SF1/J mice. F1 B6129SF1/J mice were infused for 6 days with vehicle or AngII at 300 ng/kg/day alone or in combination with S1P inhibitor PF-429242 and BP was monitored by radiotelemetry. S1P inhibition significantly attenuated AngII-induced increases in mean arterial pressure, systolic blood pressure, and diastolic blood pressure. However, a caveat is that besides PRR, S1P modifies other substrates such as unique membrane-bound latent transcription factors: sterol regulatory element-binding transcription factor, a crucial transcription factor governing cholesterol and fatty acid biosynthesis [42-45], as well as membrane-bound activating transcription factor 6 during ER stress response [46]. Although no evidence suggests involvement of sterol regulatory element-binding transcription factor or activating transcription factor 6 in AngII-induced hypertension, S1P inhibition alone could not prove a causal role of sPRR in this model. To address this concern, supplement of sPRR-His was administered to PF-429242 treated mice, leading to partial restoration of the hypertensive response to AngII. Furthermore, AngII infusion stimulated sPRR production as reflected by increased urinary sPRR excretion and renal medullary sPRR abundance, which was suppressed by PF-429242 treatment. Together, the results from the pharmacological study strongly support sPRR as an important mediator of AngII-induced hypertension.

Recently, the role of sPRR in AngII-induced hypertension was verified by two independent mouse models with mutagenesis of the cleavage site of PRR [47, 48]. We employed CRISPR/Cas9 strategy to generate mice with mutagenesis of the overlapping cleavage site for S1P and furin in PRR (termed as PRRR279V/L282V) [48]. PRRR279V/L282V mice that exhibited a reduction of sPRR level in plasma by ∼53% and in the kidney by ∼82% were fertile and had no gross developmental abnormalities. As compared with their wild-type (WT) controls, the mutant mice had blunted hypertensive response to AngII infusion. Ramkumar et al. [47] employed a similar strategy to produce mutagenesis of the overlapping cleavage site for S1P and furin in PRR albeit with different amino acids. Despite differences in the magnitude of the reduction of sPRR in the circulation and different tissues, the blockade of AngII-induced hypertension was quite similar as reported by the two studies. The new evidence from the two genetic studies has substantiated the essential role of sPRR in AngII-induced hypertension. However, since the cleavage site for both S1P and furin is mutated in these studies, the relative importance of S1P versus furin remains unknown and certainly warrants further investigation, ideally through a more precise mutagenesis of the cleavage site for a specific protease without affecting another one. While compelling evidence supports S1P as a predominant source of sPRR [21, 49], the role of furin is quite controversial [21, 49].

Despite the consistent BP phenotype associated in the above-mentioned two strains of sPRR mutant mice, the data on the site of reduced sPRR production in the two models still needs to be reconciled. For example, renal sPRR was drastically reduced in one model [48] but was almost unaffected in another [47]. In our study, the reduced renal sPRR production was consistent with the data supporting involvement of renal mechanism involving suppressed intrarenal RAS and α-ENaC expression. To address the potential vascular mechanism involved in the BP phenotype of PRRR279V/L282V mice, we examined the pressor response to acute AngII treatment under conscious condition using radiotelemetry. The acute pressor response induced by s.c. injection of AngII at 30 µg/kg was comparable between the two genotypes, indicating intact vasoconstrictive response. However, the sPRR model generated by Ramkumar et al. [47] showed normal sPRR level in the kidney contrasting to undetectable circulating sPRR, suggesting involvement of extra-renal sources of sPRR. Along this line, these investigators conducted isolated vessel myograph experiments and presented evidence for altered vascular response in the sPRR mutant model with reduced AngII-induced vasoconstriction and enhanced acetylcholine-induced vasorelaxation. Additionally, the pattern of changes in body weight was totally opposite with obese phenotype in one model and lean phenotype in another model. The reason for this discrepancy remains unclear. We have previously shown that adipose-derived sPRR plays a major role in regulation of energy metabolism. The metabolic action of sPRR was originally suggested by enhanced beiging in white adipose tissues induced by administration of sPRR-His in C57/BL6 mice [33]. The potential metabolic benefit of sPRR observed in C57/BL6 mice prompted a subsequent study using a model of diet-induced obesity (DIO). Administration of sPRR-His to DIO mice promotes energy expenditure, reduced body weight, enhanced insulin sensitivity, and therefore improved hyperglycemia, hepatic steatosis, as well as diabetic kidney disease in DIO [35]. The beneficial metabolic action of sPRR seems compatible with the obese phenotype in PRRR279V/L282V mice. However, the mechanism of reduced body weight in Ramkumar’s sPRR mutant model was unexplained [47].

sPRR in Obesity Hypertension

Over the past several decades, the prevalence of obesity has reached global epidemic largely due to decreases in physical activity and increases in energy intake. Nearly one-third of the adults are obese and over 60% are overweight in the United States [50-52]. Landmark epidemiological studies such as National Health and Nutrition Examination Survey (NHANES) and the Framingham Heart Study propose a tight association between body weight and BP [53]. Obesity may account for as much as 60–70% of the risk for essential hypertension [53-55]. The molecular basis for the link between obesity and hypertension appears complex and may involve interplay of multiple factors such as sympathetic nervous system (SNS), the RAS, inflammation, oxidative stress, microbiome, etc. [55-60].

Evidence from both animal and human studies is available to suggest a potential role of sPRR in obesity hypertension. Circulating sPRR is elevated in mice on a high fat diet (DIO) [34, 37]. Two independent groups consistently demonstrated that administration of a recombinant sPRR increased BP by ∼10 mm Hg in DIO mice [37, 61] but not in lean controls [37], suggesting that the prohypertensive action of sPRR is dependent on the metabolic milieu. In 23 patients with sleep apnea and morbid obesity, bariatric surgery reduced plasma sPRR from 15.3 ± 3.6 to 12.5 ± 2.7 ng/mL 4 weeks after surgery, which further decreased to 11.4 ± 2.4 ng/mL 24 weeks after surgery [62], representing indirect evidence supporting the association between obesity and sPRR. Evidence is also available to address the source and mechanism of sPRR production. We have shown that PRR is a molecular target of PPARγ in adipocytes as highlighted by a 70% reduction of circulating sPRR by adipocyte-specific deletion of PPARγ [35]. The opposite is true that adipose PRR expression and plasma sPRR are both elevated by rosiglitazone (Rosi) treatment [35]. It seems reasonable to speculate that increased sPRR in obesity may derive from activation of PPARγ in adipose tissues. Apart from adipose tissues, obesity may induce sPRR production in the kidney. This possibility is supported by the observation that renal PRR expression was elevated in DIO mice [63]. The relative importance of different sources of sPRR, particularly the adipose tissue versus the kidney, in obesity hypertension warrants future investigation (Fig. 1, 2).

Fig. 1.

Schematic illustration of the proposed role of sPRR in AngII-induced hypertension. Following AngII infusion, the abundance of PRR and sPRR is elevated in the renal medulla, possibly the intercalated cells but not renal cortex. sPRR may act in a paracrine manner to rapidly elevate ENaC activity and chronically increases α-ENaC transcription in the principal cells of the CD to induce Na+ retention and hypertension.

Fig. 2.

Schematic illustration of the proposed role of sPRR in obesity hypertension. Circulating sPRR is elevated in obese animals and may contribute to elevated BP through multiple mechanisms involving renal Na+ retention, EC dysfunction, and BRS impairment.

How does increased sPRR contribute to obesity hypertension? Multiple mechanisms have been proposed to explain the prohypertensive action of sPRR in obesity which involves activation of ENaC, induction of endothelial dysfunction, and impairment of baroreflex response. Each of these mechanisms will be discussed in the following.

sPRR Activation of ENaC in Obesity

There is consensus that increased Na+ reabsorption by the kidney plays a major role in pathogenesis of obesity hypertension [55, 56, 64]. As in many other forms of hypertension, impairment of pressure natriuresis due to increased renal tubular Na+ reabsorption contributes to increased BP in obesity. While the site of such renal Na+ retention remains elusive, accumulating evidence from animal studies suggests that the distal nephron may be a primary site of Na+ retention in obesity [65]. Indeed, the CD as the terminal part of the nephron plays a pivotal role in homeostatic control of fluid, electrolyte balance, and BP under various physiopathological conditions. In support of this notion, high-fat-fed dogs exhibited increased Na+ reabsorption in the absence of changes in renal hemodynamics or fractional lithium excretion, an index of proximal tubular reabsorption [66]. In db/db mice, dysregulation of ENaC, a major route for Na+ reabsorption in the apical membrane of the CD, contributes to salt-sensitive hypertension [67]. Clinical evidence further shows that obesity hypertension is often resistant to conventional antihypertensive therapy, consisting of a β-blocker, and angiotensin-converting enzyme inhibitor or an AngII receptor blocker or a diuretic (usually hydrochlorothiazide), a condition termed as resistant hypertension [68]. Case reports show that refractory hypertensive individuals with hyperactive ENaC activity in lymphocytes responded positively to amiloride [69]. Subsequently, a prospective, randomized, double-blind, placebo-controlled clinical trial demonstrated the effectiveness of inhibiting ENaC function with spironolactone or amiloride for improving BP control in black Americans (all of whom were clinically obese) [70]. Together, evidence from both animal and human studies supports involvement of ENaC in obesity hypertension.

Indirect evidence suggests a potential role of sPRR in regulation of ENaC in obesity. In this regard, the circulating level of sPRR in DIO mice is clearly elevated despite its unknown source [37]. Abundant evidence from in vitro studies has demonstrated that sPRR rapidly increases ENaC activity through activation of NOX-4-derived H2O2 and chronically induces α-ENaC transcription via β-catenin signaling [71]. Together, these results seem to suggest sPRR as a potential mediator of obesity hypertension. However, direct evidence for a causal role of sPRR in this disease is still missing. Ideally, this issue can be addressed by inhibition of endogenous production of sPRR through pharmacological inhibition of S1P or mutagenesis of the cleavage site of PRR [48] and examination of the impact on BP in obese animals.

As opposed to the stimulatory effect of PRR/sPRR on renal expression of α-ENaC as well as other Na+ and water transporters and its related proteins such as aquaporin-2, vasopressin receptor type 2, Na/K/2Cl cotransporter, and Na/H exchanger 3 [10, 72-74] under various experimental conditions, sPRR inhibits phosphorylation of Na-Cl cotransporter, promoting the kaliuretic response to high K+ loading and potentiating the hypertensive response to high salt loading [75]. Activation of Na-Cl cotransporter by WNK kinase-OSR/SPAK cascades [76] or the renin-angiotensin-aldosterone system [77] is known to contribute to the maintenance of Na+ balance and development of salt-sensitive hypertension. Together, PRR/sPRR can exert both stimulatory and inhibitory effects on expression/activity of renal transporters depending on physiological contexts.

sPRR Induction of Endothelial Dysfunction

Endothelial cells (ECs) lining the vascular wall serve a barrier function and actively regulate vascular tone, blood flow, and platelet function. Dysregulation of ECs contributes to pathogenesis of various pathological conditions and is a hallmark of obesity hypertension. Loss of endothelium-dependent vasodilation is commonly observed in obese patients [78, 79] and animals [80, 81] and is thought to be a major contributor to obesity hypertension. Multiple factors such as oxidative stress, inflammation, leptin resistance, and AngII all contribute to obesity-induced endothelial dysfunction. A better understanding of the precise driver of endothelial dysfunction will realize new strategies for therapeutic intervention of obesity hypertension.

Within the vasculature, PRR is abundantly and specifically expressed in the vascular smooth muscle cells (VSMCs) but not ECs [1]. We have reported that cultured VSMCs released sPRR in response to AngII, which was attenuated by PRR inhibition [9]. Therefore, these results may suggest a possible paracrine mechanism whereby VSMC-derived sPRR may induce endothelial dysfunction, which plays an important role in the development of hypertension [31, 38, 58]. Recently, we for the first time assessed the role of sPRR in primary human umbilical vein endothelial cells (HUVECs) [37]. HUVECs exposed to sPRR-His exhibited pro-inflammatory response as highlighted by activation of NF-κB and subsequent elevation of IL-6, IL-8, VCAM-1, and ICAM-1 mRNA expression, accompanied with reduced NO production and enhancement of apoptosis [37]. These responses were secondary to sPRR-His-evoked elevations in NOX4-derived H2O2 production. In agreement with this observation, another study from our group reported that NOX-4 was involved in sPRR-mediated acute upregulation of ENaC activity in cultured mpkCCD cells [71]. Interestingly, β-catenin signaling but not NOX4 contributes to sPRR-induced transcriptional upregulation of α-ENaC expression [71]. Therefore, sPRR may induce distinct signaling pathways to coordinate the regulation of activity and expression of ENaC. Along this line, sPRR directly interacted with frizzle-8 to induce β-catenin signaling to upregulate aquaporin-2 transcription in cultured CD cells [10]. Despite the well-demonstrated role of β-catenin signaling in mediating the action of sPRR in the CD cells, there is no evidence to support existence of the same sPRR/β-catenin-mediated mechanism in ECs. Likely, sPRR may induce diverse signaling pathways depending on the cell type.

The AT1R is a core member of the RAS, mediating most of the known actions of AngII including those in promoting endothelial dysfunction [82]. In the classic sense, AngII has been traditionally thought to be the exclusive ligand for the AT1R. Interestingly, AT1R antagonism with losartan effectively abrogates most of the deleterious effects of sPRR-His in cultured HUVECs as described above, although AngII level was unaffected by sPPR-His. This unexpected finding led to a breakthrough discovery that sPRR directly interacted and activated the AT1R in cultured HUVECs [37]. Site-directed mutagenesis elucidated Lysine199 and Asparagine295 in the AT1R as the key amino acids for biding to sPRR. Lysine199 is known to be important for binding to AngII and losartan [37]. This is the first report on the direct interaction between sPRR and the AT1R in general, and in ECs in particular and may challenge the concept about AngII as the exclusive physiological ligand of the AT1R [31, 71].

In vivo evidence is also available to support importance of the AT1R in mediating prohypertensive action of sPRR-His in DIO mice [37]. In this regard, sPRR-His-induced elevation of BP was reversed by concurrent treatment with losartan but not ACEi using captopril. The distinct effects of losartan versus captopril strongly support that sPRR induces hypertension via direct activation of AT1R as opposed to the generation of AngII. Consistent with these results, isometric tension techniques revealed that endothelium-dependent vasodilation displayed by arteries from DIO mice treated with sPRR-His was improved by losartan. In contrast, vascular smooth muscle responses were similar between groups. These results support ECs but not VSMCs as the primary site of action of sPRR.

sPRR Induction of Baroreflex Impairment in Obesity

There is abundant evidence indicating an essential role of the SNS activity in pathogenesis of obesity hypertension [55, 83]. In this regard, a meta-analysis involving 1,438 obese or overweight subjects recruited in 45 microneurographic studies showed that compared with normoweights, muscle sympathetic nerve traffic was significantly greater in overweight and more in obese individuals as assessed by nerve traffic recording of muscle sympathetic nerve traffic [84]. Renal sympathetic activity was similarly elevated in obese rats and shown to be a predictor of sympathoexcitation and obesity hypertension [85]. The contribution of sympathoexcitation to obesity hypertension is highlighted by the BP-lowering effect of administration of α/β-adrenergic blockers in obese patients and animals [86]. Furthermore, renal denervation markedly attenuates sodium retention and hypertension in obese animals [87] and obese patients with resistant hypertension [88]. However, despite intensive investigation, the mechanism of obesity-induced sympathoexcitation remains to be incompletely understood.

The baroreceptor-mediated baroreflex response, also known as baroreflex sensitivity (BRS), represents a rapid negative feedback system, playing an essential role in homeostatic control of BP by minimizing BP variations via modulation of the SNS activity. Dysregulation of BRS has been reviewed as a key mechanism driving the SNS activity and hypertension in obesity. Randomized clinical trials have shown that obesity significantly decreased BRS [89]. In addition, the adoption of a hypocaloric diet resulted in improvement of BRS in obese patients [90]. Given the important role of BRS, technology has been developed to electrically stimulate the carotid baroreflex to suppress the SNS activity and treat hypertension including obesity hypertension [88]. Observational trials have yielded promising results with this technology, which need to be confirmed in larger, adequately powered, sham-controlled trials [91].

Gatineau et al. [34] recently reported the central action of sPRR in obese mice. In this study, spontaneous BRS was examined in obese C57BL/6 male mice infused with vehicle or sPRR using the sequence method described by Bertinieri et al. [92]. Spontaneous BRS was found to be lower following sPRR treatment as compared with vehicle control. A ganglionic blocker chlorisondamine produced a greater fall in BP in sPRR-infused mice. These results seem to support that sPRR infusion potentiated obesity associated sympathoexcitation via impairment of BRS. In agreement with this observation, accumulating evidence supports central action of PRR in regulation of BP [93, 94]. In particular, activation of the PRR in the paraventricular nucleus increases sympathetic outflow in anesthetized rats [95]. Furthermore, PRR knockdown in the brain or intracerebroventricular infusion of PRO20 lowered BP in rodent models of hypertension induced by deoxycorticosterone acetate salt treatment or transgenic overexpression of human renin and angiotensinogen [96, 97]. However, obese mice infused with sPRR showed no change in brain sPRR protein abundance, which may argue against the idea that sPRR passed through blood-brain barrier to exert its direct action on the SNS. An alternative mechanism has been proposed that sPRR may indirectly activate the SNS via leptin, a known regulator of sympathetic tone in obesity [98]. In support of this possibility, sPRR infusion elevated plasma leptin in obese mice [34]. How and where does sPRR stimulate leptin production? To what extent does leptin contribute to the central action of sPRR? These questions warrant further investigation in the future.

Summary

Evidence is beginning to emerge to support novel physiopathological roles of sPRR, the cleavage product of the full-length PRR. The functional contribution of sPRR to AngII-induced hypertension has been firmly established by using pharmacological inhibition of S1P and mutagenesis of the cleavage site in PRR. sPRR mediation of the hypertensive response to AngII infusion mainly relies on renal mechanisms involving activation of renal medullary ENaC and the intrarenal RAS. In addition, indirect evidence suggests involvement of sPRR in pathogenesis of obesity hypertension. In this regard, circulating sPRR is elevated in obese mice, and administration of a recombinant sPRR produces a small but significant increase in BP only in obese but not lean animals. The pressor effect of sPRR in obesity may depend on multiple mechanisms involving renal Na+ retention, EC dysfunction, and baroreflex impairment. However, more definitive evidence is needed to address the contribution of endogenously produced sPRR to obesity hypertension and to further define the precise underlying mechanism. Understanding the role of sPRR in the two animal models of hypertension will pave the way to define this soluble protein as a common downstream mediator of Na+ retention and hypertension under various types of hypertensive stimuli. Therefore, targeting sPRR production or/and action may hold promise for development of novel antihypertensive therapies.

Conflict of Interest Statement

The author declares no conflict of interest.

Funding Sources

This work was supported by National Institutes of Health Grants DK104072 and DK094956, VA Merit Review from the Department of Veterans Affairs, and National Natural Science Foundation of China Grants No. 91439205 and No. 31330037. T. Yang is a Research Career Scientist in the Department of Veterans Affairs.

Author Contributions

T. Yang is the sole contributor to this review.

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