Prorenin: back into the arena.

Prorenin, the precursor of renin, exists in circulating blood at concentrations that are 5 to 10 higher than those of renin. For many years, prorenin was considered to be an inactive form of renin with no physiological role. Then, in the mid-80s of the last century, Luetscher et al reported that the levels of circulating prorenin (but not renin) are increased in diabetic subjects.1 Subsequent studies revealed that these high levels correlated with the presence of microvascular complications, and it was proposed that prorenin might be used to predict the occurrence of microalbuminuria.2 Simultaneously, high prorenin levels were observed in pregnant women, and evidence was obtained for the local synthesis of prorenin at extrarenal tissue sites such as the ovary and eye. Until today, however, the exact function of prorenin remains unknown. An attractive concept is that in tissues not synthesizing renin locally, circulating prorenin, after its local conversion to renin, contributes to angiotensin (Ang) generation. This would not only provide a role for prorenin in vivo, but also explain why tissues, in contrast with plasma, contain predominantly renin.3 Studies in transgenic animals support this idea. Véniant et al4 described that transgenic rats expressing prorenin exclusively in the liver (resulting in a 400-fold rise in plasma prorenin) display cardiac hypertrophy and vascular damage in the absence of hypertension. Prescott et al5 detected increased cardiac Ang I levels in mice overexpressing human prorenin in the liver and human angiotensinogen in the heart. The question then arises how tissues sequester and activate circulating prorenin. Sequestration may involve diffusion into the interstitial fluid and/or binding to a receptor.3 Activation can occur in 2 ways (Figure 1): the prosegment is proteolytically cleaved, or the prosegment unfolds from the enzymatic cleft, thus allowing intact prorenin to become catalytically active (nonproteolytic activation). The latter process is pHdependent and might be enhanced at tissue sites (eg, in the extracellular matrix). A nonrenal prorenin-cleaving enzyme has not yet been demonstrated. Two recent studies have provided the missing pieces of the above puzzle. First, Nguyen et al6 identified a renin receptor that bound renin and prorenin equally well. Interestingly, prorenin, when bound to this receptor, displayed enzymatic activity although there was no evidence for proteolytic cleavage of the prosegment. Thus, receptor binding per se may have resulted in a conformational change of the prorenin molecule, thereby enabling it to become catalytically active (Figure 2). Second, investigators in Japan7 developed a decoy peptide corresponding with the handle region in the prorenin prosegment (handle region peptide [HRP]). This region supposedly interacts with a receptor, thereby enabling prorenin to undergo nonproteolytic activation. HRP blocks this in a competitive manner. Consequently, any Ang I generation that is attributable to receptor-bound, nonproteolytically activated prorenin will be suppressed. Indeed, HRP reduced the renal content of Ang I and II and fully prevented the development of diabetic nephropathy in streptozotocin-induced diabetic rats.7 Surprisingly, HRP did not affect the plasma levels of Ang I and II in diabetic rats, nor the renal tissue Ang I and II levels in control rats. To explain the latter, the authors propose that the prorenin–renin ratio is altered in the diabetic rat kidney (for instance, attributed to a reduction in the prorenin-renin converting enzyme cathepsin B), thereby allowing more prorenin to bind to the receptor. The receptor identity was not investigated in this study.7 In the current issue of Hypertension, Ichihara et al8 now bring the renin receptor described by Nguyen et al6 and HRP together. The authors treated 4-week-old stroke-prone spontaneously hypertensive rats (SHRsp) with HRP, and observed a reduced cardiac Ang content and fibrosis after 8 weeks of treatment, with no change in blood pressure or the levels of circulating Ang. HRP exerted no effect in Wistar-Kyoto (WKY) controls. Interestingly, at 8 weeks of age, when no organ damage was present in SHRsp, their cardiac renin receptor mRNA levels were 3 higher than in WKY controls. Since this difference disappeared at age 12 weeks, the authors propose that the interaction between prorenin and its receptor contributes to the development, but not the progression, of cardiac damage in the SHRsp. To support the idea that HRP exerted its effects in SHRsp by blocking nonproteolytic activation of prorenin, Ichihara et al provide immunohistochemical data specific for the prosegment and the active site of renin. HRP did not alter prosegment immunoreactivity, and reduced active site immunoreactivity to WKY levels. The reduction in active site immunoreactivity paralleled the reduction in cardiac Ang content. Unfortunately, the study does not reveal whether the active site immunoreactivity represents nonproteolytically activated prorenin or renin, nor do the immunohistochemical studies provide a quantitative comparison between prosegment immunoreactivity and active site immunoreactivity. Thus, an The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pharmacology, Erasmus MC, Rotterdam, The Netherlands. Correspondence to Dr A.H.J. Danser, Department of Pharmacology, Rm EE1418b, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: [email protected] (Hypertension. 2006;47:824-826.) © 2006 American Heart Association, Inc.