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NDT Advance Access originally published online on January 27, 2007
Nephrology Dialysis Transplantation 2007 22(5):1288-1292; doi:10.1093/ndt/gfl846
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Prorenin and the (pro)renin receptor—an update

A. H. Jan Danser, Wendy W. Batenburg and Joep H. M. van Esch

Department of Pharmacology, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

Correspondence and offprint requests to: Prof. Dr A. H. J. Danser, PhD, Department of Pharmacology, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Email: a.danser{at}erasmusmc.nl

Keywords: angiotensin; diabetes; fibrosis; heart; hypertrophy; kidney; MAP kinase; prorenin; (pro)renin receptor; renin



   Introduction
Top
 Introduction
What does prorenin do?
 The (pro)renin receptor
 Angiotensin-independent effects...
 Summary and future prospects
 References
 
Blockers of the renin–angiotensin system (RAS) are widely used for the treatment of cardiovascular and renal diseases. It is generally assumed that the beneficial effects of these drugs are due, at least in part, to blockade of the generation or action of angiotensin (Ang) II at tissue sites [1]. According to this concept, Ang II is generated at tissue sites rather than in circulating blood. Multiple lines of evidence support this idea [2–5]. Remarkably, however, although several RAS components are locally expressed [e.g. ACE, Ang II type 1 (AT1) and type 2 (AT2) receptors] [6–8], thereby allowing such local activity, renin is not [9,10]. Thus, the renin required for local Ang production is sequestered from the circulation, i.e. is kidney-derived. Importantly, renin has an inactive precursor, prorenin. Prorenin is released constitutively from the kidney, and its blood plasma levels are {approx}10-fold higher than those of renin [11].



   What does prorenin do?
Top
 Introduction
 What does prorenin do?
The (pro)renin receptor
 Angiotensin-independent effects...
 Summary and future prospects
 References
 
For many years, prorenin was simply considered to be the inactive precursor of renin, without having a function of its own. Chronic stimulation of the RAS usually increases renal prorenin–renin conversion, thereby decreasing the relative amount of prorenin in the circulation. However, there are some exceptions to this rule. A very striking example is diabetes mellitus complicated by retinopathy and nephropathy [12–14]. In microalbuminuric diabetic subjects, prorenin is increased out of proportion to renin. This increase starts before the occurrence of microalbuminuria, and the prorenin level, in conjunction with the glycated haemoglobin level, might even be used to predict the occurrence of later microalbuminuria [15]. This finding suggests that prorenin does have a function after all. Pregnant women also have high plasma prorenin levels, derived from the ovaries [16,17]. Based on the latter finding, it was speculated that the high prorenin levels in diabetic subjects also originate from extrarenal sites, e.g. the eye, where prorenin then might exert an effect. Yet, although subsequently prorenin synthesis was confirmed in the eye [18], it seemed impossible, given the low ocular blood flow, that the eye could be held fully responsible for the rise in prorenin in diabetics. Thus, plasma prorenin in diabetic subjects may still largely originate in the kidney, although at present other extrarenal prorenin-releasing sites (notably, the adrenal), cannot be excluded.

It seems reasonable to assume that, if prorenin has a function, this is related to Ang generation. In this regard, it is of interest to note that the renal vasodilator response to captopril in diabetic subjects correlates better with plasma prorenin than with plasma renin [19]. This suggests that (circulating) prorenin contributes to renal Ang generation. The question then arises how this might occur. Is prorenin converted to renin at renal (or even extrarenal) tissues sites? Of course, it is well-known that prorenin–renin conversion occurs in the kidney. However, this happens before renin is released from the juxtaglomerular cells. Several enzymes have been proposed to be responsible for this proteolytic cleavage step, including proconvertase 1 and cathepsin B [20,21]. Infusion of recombinant prorenin into cynomolgus monkeys however, did not result in prorenin–renin conversion [22], and blood plasma of nephrectomized subjects contains only prorenin [23]. Thus, mechanisms other than proteolytic cleavage are required to understand why prorenin might contribute to renal plasma flow in an Ang-dependent manner. Indeed, prorenin activation may also occur in a (reversible) non-proteolytic manner, i.e. not requiring the irreversible proteolytic cleavage step. Depending on pH and temperature, prorenin is capable of undergoing a conformational change, involving the unfolding of the prosegment from the enzymatic cleft (Figure 1). Such non-proteolytically activated prorenin is fully enzymatically active.


Figure 1
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  		Fig. 1. Proteolytic and non-proteolytic activation of prorenin. Aog, angiotensinogen; Ang, angiotensin.

 
The next piece of the prorenin puzzle was discovered when Nguyen et al. [24] identified a renin receptor that bound both renin and prorenin. Unexpectedly, prorenin, when bound to the receptor, displayed enzymatic activity without proteolytic removal of the prosegment.



   The (pro)renin receptor
Top
 Introduction
 What does prorenin do?
 The (pro)renin receptor
Angiotensin-independent effects...
 Summary and future prospects
 References
 
The idea of a (pro)renin binding protein/receptor contributing to renin/prorenin uptake in tissues is not new, since already >20 years ago it was observed that vascular renin disappeared more slowly than circulating renin, following a bilateral nephrectomy [25]. In fact, several candidates for such a binding/uptake mechanism have been proposed throughout the years, including an intracellular renin-binding protein (RnBP) [26] and the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) [27–29]. The intracellular RnBP was eventually found to inhibit renin and its deletion affected neither blood pressure nor plasma renin [30]. Furthermore, the M6P/IGF2R, which binds phosphomannosylated (M6P-containing) proteins (like renin and prorenin), indeed bound and internalized renin and prorenin. Such binding however, did not result in Ang generation, either intracellularly or extracellularly, and it is now believed that the M6P/IGF2R serves as a clearance receptor for renin/prorenin [31].

This leaves the recently cloned (pro)renin receptor as the most promising candidate for tissue uptake of circulating renin/prorenin. This receptor, a 350-amino acid protein with a single transmembrane domain, was first identified on cultured human mesangial cells [24]. The receptor binds prorenin with higher affinity than renin [32] and, unlike the M6P/IGF2R, does not internalize these proteins. Since binding to the receptor allowed prorenin to become catalytically active without proteolytic cleavage of the prosegment, the activation must have been due to a conformational change. Interestingly in this regard, an 8.9 kDa fragment of the (pro)renin receptor called M8-9 is known to co-precipitate with a vacuolar proton-ATPase (V-ATPase) [33]. V-ATPases play important roles in acidification of intracellular compartments and cellular pH homeostasis, thereby providing a potential link between the (pro)renin receptor and acid activation. Since there is only one gene for the (pro)renin receptor and the M8-9 protein, it is likely that both proteins derive from the same transcript. The M8-9 fragment corresponds to the cytoplasmic domain, the transmembrane domain and part of the extracellular domain of the receptor.

After the discovery of the receptor, (pro)renin receptor antagonists were designed based on the idea that the prosegment contains a handle region which binds to the receptor, allowing prorenin to become catalytically active in a non-proteolytic manner [34,35]. These (peptidic) antagonists (also known as ‘handle region peptides’, HRP) mimic the handle region, and thus will bind to the receptor instead of prorenin, thereby preventing receptor-mediated prorenin activation. In support of this concept, HRP infusion normalized the elevated renal Ang content in diabetic rats [34], as well as the elevated cardiac Ang content in stroke-prone spontaneously hypertensive rats [35], without affecting blood pressure. Concomitantly, the development of diabetic nephropathy and cardiac fibrosis was prevented, suggesting that these phenomena depend on prorenin-induced tissue Ang generation. For reasons that are currently unknown, HRP infusion did not affect Ang II levels in circulating blood, nor in tissues of Wistar–Kyoto control rats. This was unexpected, since circulating Ang are largely derived from tissue sites [36], and prorenin is easily detectable in Wistar–Kyoto rats. Furthermore, since renin also binds to the receptor, it is important to find out whether HRP interferes with renin binding, and what percentage of the receptors is occupied by renin, particularly in the kidney.



   Angiotensin-independent effects of prorenin
Top
 Introduction
 What does prorenin do?
 The (pro)renin receptor
 Angiotensin-independent effects...
Summary and future prospects
 References
 
Transgenic rodents with (inducible) hepatic prorenin expression display increased cardiac Ang I levels, cardiac hypertrophy and/or vascular damage [37–39], in full agreement with the concept of circulating prorenin inducing local (cardiac and vascular) effects. Remarkably, some of these effects occurred independently of changes in blood pressure, suggesting that Angs were not involved, despite the presence of high prorenin levels. Thus, perhaps prorenin also exerts direct, Ang-independent effects, for instance via the above described (pro)renin receptor.

Indeed, both renin and prorenin induced p42/p44 mitogen-activated protein kinase (MAPK) activation and transforming growth factor (TGF)-ß1 release in mesangial cells in the presence of renin inhibitors, ACE inhibitors and/or AT1 receptor antagonists [24,40]. TGF-ß1 in turn, stimulated increases in plasminogen-activator inhibitor-1 (PAI-1), fibronectin and collagen 1 (Figure 2). Moreover, in cardiomyocytes, prorenin concentration-dependently activated p38 MAPK and simultaneously phosphorylated heat shock protein (HSP) 27 [41]. HSP27, through its regulation of actin filament dynamics, is believed to be involved in maintaining the integrity of cell architecture, growth, motility, survival and death [42]. Proteome differential display experiments performed on cardiomyocytes after 48 h of prorenin stimulation, supported the downstream effects of HSP27 on actin cytoskeleton (Figure 2) [41].


Figure 2
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  		Fig. 2. Potential (pro)renin-induced effects mediated via (pro)renin receptors, which do not involve Ang generation. See text for abbreviations.

 
Furthermore, the above described beneficial effect of (pro)renin receptor antagonists on diabetic nephropathy also occurred in AT1A receptor-deficient mice [43]. Since such mice no longer display the normal (constrictor) response to Ang II [44], the effect of the (pro)renin receptor antagonist in these mice cannot be explained solely on the basis of suppression of local Ang generation. Interestingly, phospho-p42/p44 MAPK as well as phospho-p38 MAPK and phospho-Jnk MAPK were up-regulated in the diabetic kidney, both in WT mice and in AT1A receptor-deficient mice, and (pro)renin receptor blockade (but not ACE inhibition) fully normalized this increased phosphorylation [43]. Finally, Schefe et al. [45] identified the transcription factor promyelocytic zinc finger (PLZF) protein as a direct protein interaction partner of the C-terminal domain of the (pro)renin receptor by yeast 2-hybrid screening and coimmunoprecipitation. Importantly, on activation of the receptor by renin, PLZF is translocated to the nucleus and represses transcription of the (pro)renin receptor itself, thus creating a short negative feedback loop. In other words: high renin levels, as occurring during RAS blockade, will suppress (pro)renin receptor expression, thereby preventing excessive receptor activation. Whether prorenin exerts the same effect is currently unknown.

Overexpression of the human (pro)renin receptor in rats resulted in elevated blood pressure, increased plasma aldosterone and/or increased cyclooxygenase-2 expression in the renal cortex [46,47]. Since such overexpression was not accompanied by changes in plasma renin activity or tissue Ang II content, Ang-independent effects of the receptor may underlie this phenotype.



   Summary and future prospects
Top
 Introduction
 What does prorenin do?
 The (pro)renin receptor
 Angiotensin-independent effects...
 Summary and future prospects
References
 
After many years, it now seems that a function for prorenin has been found. The ‘inactive’ renin precursor gains Ang I-generating activity by binding to a receptor, without undergoing proteolytic cleavage. Receptor binding, like low pH and low temperature, induces conformational changes in the prorenin molecule, leading to the unfolding of the prosegment from the enzymatic cleft. This change is reversible, and receptor binding (and subsequent prorenin activation) can be blocked with a (pro)renin receptor blocker. The idea of prorenin contributing to tissue Ang generation is attractive, because it puts the much higher prorenin than renin levels (particularly in diabetic subjects with microvascular complications) into perspective. However, it does not answer the question why prorenin levels are elevated in diabetic subjects in the first place.

Unexpectedly, renin–prorenin binding to the (pro)renin receptor also activates intracellular signalling pathways in an Ang-independent manner. To what extent renin and prorenin exert identical effects is currently unknown. Direct prorenin-induced effects on fibrosis, growth and development provide an explanation for the Ang II- and blood pressure-independent cardiovascular damage observed in rats overexpressing prorenin or the (pro)renin receptor [39,46]. Combined with the concept that prorenin becomes activated when bound to the (pro)renin receptor [24,34], a new class of drugs might emerge, i.e. (pro)renin receptor blockers, which prevents both Ang generation at tissue sites and (pro)renin-induced, Ang-independent effects.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 What does prorenin do?
 The (pro)renin receptor
 Angiotensin-independent effects...
 Summary and future prospects
 References
 

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Received for publication: 21.12.06
Accepted in revised form: 31.12.06


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