Prorenin and glomerulosclerosis?

The recognition of two new components of the renin–angiotensin system (RAS), the (pro)renin receptor [1] and a new class of RAS blockers, the renin inhibitors [2,3], has propelled the pathological role of prorenin into the spotlight. Although it is well established that circulating renin cleaves angioteninogen into angiotensin I (Ang I) the precursor of Ang II, the biological activities and importance of prorenin remain to be fully defined. Speculation that prorenin plays a role in cardiac and renal fibrosis and in hypertensive and diabetic nephropathy has been difficult to explain in the absence of a mechanism. It is now becoming apparent that the (pro)renin receptor may provide the missing component of the local RAS and explain at least some of the biological activities associated with high levels of prorenin. In this issue of the journal, Peters et al.[4] using the transgenic rat strain, Cyp1a1-Ren2, provide evidence that prorenin dose-dependently increases blood pressure with no apparent effect on the development of glomerulosclerosis. The mechanisms by which these rats develop high blood pressure are not clear but binding and activation of the (pro)renin receptor must be a strong contender. Perhaps more intriguing, given other recent publications [5], is the absence of glomerulosclerosis in this model. Prorenin is generally viewed as the inactive precursor of renin with the 43-amino acid N-terminal propeptide blocking the enzymatic cleft and obstructing access of angiotensinogen to the active site of renin. Despite this, circulating levels of plasma prorenin represent 70–90% of total renin and up to 95% in diabetic patients. The association of these high prorenin levels with the development of microvascular complications in diabetics has been instrumental in the suggestion that prorenin itself has a pathological role [6–8]. In support of this, transgenic rodents with high circulating levels of liver-derived prorenin were shown to display increased tissue Ang I levels associated with cardiac hypertrophy and/or vascular damage [9,10]. The report by Peters et al.[4] further explores the roles of prorenin. In their study, Cyp1a1-Ren-2 rats were treated with different doses of indole-3-carbinol to dose-dependently induce the prorenin transgene. Despite reductions in circulating renin levels, aldosterone was increased, as were levels of blood pressure. How could elevations in circulating prorenin induce changes in blood pressure? The authors suggest that the raised levels of aldosterone may arise through activation of local RAS by prorenin. It is now clear that prorenin can be activated in two ways: (i) proteolytic and (ii) nonproteolytic. Proteolytic involves the cleavage of the propeptide sequence, as occurs in the kidney prior to release of renin. The low levels of renin indicate that this does not occur in this model. Nonproteolytic activation consists of an unfolding of the propeptide from the enzymatic cleft, as occurs at the (pro)renin receptor [11]. Interestingly, when bound to the receptor, prorenin displays full enzymatic activity. The binding of prorenin to the receptor not only facilitates angiotensin generation, but also has been shown to provoke activation of p44/p42 pathways, demonstrating the Ang II-independent effects of prorenin [12]. Consequently, the binding of prorenin to this receptor may explain the pathology observed under certain conditions of low renin as observed in the study under discussion. In support of this, using streptozotocin-induced diabetic rats, Ichihara et al.[13] applied a decoy peptide to block nonproteolytic activation of prorenin and showed that not only did this reduce the renal content of Ang I and II, but also it prevented the development of diabetic nephropathy. Subsequent studies showed that blocking this receptor was capable of reversing nephropathy [14]. How can the lack of glomerulosclerosis be explained in the Cyp1a1-Ren2 model? It is intriguing to note that Peters et al.[4] used two sets of rats for their studies. The dose-dependent effects of the transgene on blood pressure, as measured by telemetry, were demonstrated in the first set with no consequence of the chemical inducer evident in the nontransgenic control group. A second set of rats, in which blood pressure was measured using femoral artery catheterization, was used to assess the RAS and renal pathology. Although the blood pressure measurements were similar using the two different methods, the authors justify the use of direct catheterization by preliminary studies being associated with an inflammatory response induced by the surgical implantation of the telemetry device itself. It is well established that radiotelemetric monitoring eliminates confounding stress effects introduced by handling, restraint and anesthesia observed using more conventional methods for blood pressure measurements. However, no method is perfect. One disadvantage of radiotelemetry for blood pressure monitoring includes this requirement for an invasive surgical procedure. As described by Peters et al.[4], this may induce inflammation, often results in the fibrotic encapsulation of the device itself and has early effects on growth and circadian rhythms [15]. Bernstein [16] measured the exercise capacity in mice before and 2 weeks after implanting telemetry devices and demonstrated a 33% reduction overall indicating that the implant is not always inert. Is it possible that the lack of an inflammatory response in the Cyp1a1-Ren2 rats is sufficient to explain the difference between these studies and others in which elevated prorenin does is associated with glomerulosclerosis? The development of glomerulosclerosis is clearly multifactorial and inflammation may well be the missing risk factor in this model. There can now be little doubt that prorenin has a physiological role in the generation of tissues RAS and maybe a pathophysiological one as well. Now that renin inhibitors are clinically available [2,3], it is of the utmost importance to learn whether these, or any other drugs, have any impact at the (pro)renin receptor. Indeed, there has already been speculation that the efficacy of the recently licensed renin inhibitor, Aliskiren, may be reduced in particular patient groups [17]. The demonstration that antihypertensive treatment of the Goldblatt rat resulted in increased expression of the prorenin receptor associated with increased circulating levels of renin and prorenin means that more work needs to be done to understand the position of prorenin and its receptor in pathophysiology [18]. Future studies of the kind performed by Peters et al.[4] will help to define that role.