Published online before print January 22, 2008, doi: 10.1161/HYPERTENSIONAHA.107.101444
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(Hypertension. 2008;51:682.)
© 2008 American Heart Association, Inc.
Original Articles |
Prorenin and Renin-Induced Extracellular Signal-Regulated Kinase 1/2 Activation in Monocytes Is Not Blocked by Aliskiren or the Handle-Region Peptide
From the Medical Faculty of the Charité (S.F., H.K., R.D., A.F., F.C.L., D.N.M.), Experimental and Clinical Research Center, Franz Volhard Clinic and HELIOS Klinikum, Berlin-Buch, Germany; Max-Delbrück-Center for Molecular Medicine (I.M., U.M., M.W., C.B., M.B., F.C.L., D.N.M.), Berlin-Buch, Germany; Institut National de la Santé et de la Recherche Médicale (A.C., G.N.), Unit 833, and Collège de France, Chaire de Médecine Expérimentale, Paris, France; and the Department of Pharmacology (W.W.B., A.H.J.D.), Erasmus MC, Rotterdam, The Netherlands.
Correspondence to Dominik N. Muller, Experimental and Clinical Research Center, Lindenberger Weg 80, 13125 Berlin, Germany. E-mail dominik.mueller{at}mdc-berlin.de
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Abstract |
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The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP). We tested whether human prorenin and renin induce extracellular signal-regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of 125I-renin or 125I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate-labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling.
Key Words: renin • prorenin • (pro)renin receptor • aliskiren • signal transduction
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Introduction |
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Aliskiren is a recent Food and Drug Administration-approved, low-molecular weight, direct renin inhibitor that binds to the enzymatically active cleft of renin. Direct renin inhibition in a double-transgenic rat model of high human renin hypertension demonstrated target organ protection.1,2 A novel (pro)renin receptor [(P)RR] has been cloned that signals when exposed to either renin or prorenin.3 The (P)RR, correctly termed "RR/ATP6AP2," is a single transmembrane domain protein of 350 amino acids with a large unglycosylated and highly hydrophobic N-terminal domain and a short cytoplasmic tail of
20 amino acids. The (P)RR is a protein conserved among species.4 The (P)RR enhances renin catalytic activity and allows prorenin to display catalytic activity without its proteolytic conversion to renin ("nonproteolytic activation"). Such nonproteolytic activation involves unfolding of the prosegment from the enzymatic cleft, mediated by a (P)RR-induced conformational change in the prorenin molecule. This (P)RR-induced prorenin activation could explain how prorenin exerts pathological effects in diabetic patients, where prorenin represents 
95% of total circulating renin. Nevertheless, this hypothesis remains to be proven. Ichihara et al5 and Suzuki et al6 developed a decoy-peptide epitope of the prorenin prosegment that they termed the "handle-region peptide" (HRP). The HRP ostensibly blocks binding of prorenin to the (P)RR.5,6 They showed that the infusion of HRP completely prevented diabetic nephropathy in rats and mice, ameliorated renal and cardiac damage in hypertensive spontaneously hypertensive rats, and improved endotoxin-induced uveitis.5,7–9 Recent data showed that renin induces activation of the extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) signaling independent of angiotensin (Ang) II.3,10,11 Huang et al10,11 also demonstrated that renin signaling was blocked by silencing the (P)RR with small-inhibiting RNA. An interaction between direct renin inhibition and (P)RR signaling has not been reported. We tested the effect of aliskiren and HRP on prorenin and renin-induced ERK 1/2 mitogen-activated protein kinase signaling in U937 monocytes.
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Methods |
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Human Renin and Prorenin
Recombinant human prorenin was produced in Chinese hamster ovary cells transfected with a vector containing human prorenin cDNA.12 Prorenin was partially purified, to remove traces of renin, by Cibacron Blue Sepharose affinity chromatography.13 The intrinsic renin activity of the prorenin preparation, before proteolytic activation, was <2% of the activity after complete proteolytic activation. Recombinant human renin was prepared by proteolytic activation of recombinant human prorenin with immobilized trypsin.14 Sepharose-bound trypsin (final concentration: 0.25 mg trypsin per milliliter) was added to the prorenin preparation; the mixture was kept at 4°C for 72 hours. Trypsin was then removed by centrifugation. Renin samples did not show prorenin. The prorenin and renin preparations were stored at –70°C.
Cell Culture and Western Blot
U937 monocytes (American Type Culture Collection CRL-1593.2) were cultured in RPMI 1640 containing 2 mmol/L of L-glutamine adjusted to contain 1.5 g/L of sodium bicarbonate, 4.5 g/L of glucose, 10 mmol/L of HEPES, and 1 mmol/L of sodium pyruvate; 10% FBS and Pen/Strep were added. All of the stimulation experiments were performed under 24-hour serum-free conditions. For stimulation experiments, cells were preincubated with the Ang II type 1 (AT1) receptor blocker losartan (10 µmol/L) and Ang II type 2 (AT2) receptor blocker PD123319 (10 µmol/L) for 30 minutes. Thereafter, cells were treated with human recombinant renin (10 nM), human recombinant deglycosylated renin (10 nmol/L) that was deglycosylated by glycosidase H and D (Dr Heinz Döbeli, Roche, Switzerland, personal communication, 2007), or human recombinant prorenin (2 nmol/L). For the analysis of the direct renin inhibitor aliskiren (10 µmol/L, Novartis), renin or prorenin was preincubated with aliskiren for 15 minutes and then administered to the cells. In all of the other inhibitor protocols, cells were preincubated with the respective blocker for 30 minutes. The following blockers were used: the HRP (1 µmol/L; NH2-RIFLKRMPSI-COOH, Biosynthan), the epidermal growth factor receptor blocker AG1478 (0.1 µmol/L), the protein kinase C (PKC) 
/β inhibitor Gö6976 (10 nM), and the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor PD98059 (10 µmol/L; all Calbiochem). After stimulation, cells were harvested and lysed with lysis buffer containing protease inhibitor Complete (Roche) and phosphatase inhibitor mixture (Sigma). For Western blotting, we used polyclonal ERK 1/2 and phospho-ERK 1/2 (both Cell Signaling). Peroxidase-conjugated secondary antibodies were purchased from Dianova. Blots were developed with chemiluminescence substrate. Three to 6 different cell stimulation experiments were performed for each protocol. Quantifications were performed with the National Institutes of Health Image program. P42/44 MAPK assay was performed following the manufacturer’s description (Cell Signaling). Binding experiments were performed as described earlier.15 The concentration of labeled renin and prorenin was 0.1 to 0.2 nmol. Cold renin (1 µmol/L) could inhibit prorenin binding by 100%, and 350 nmol/L of cold prorenin could inhibit renin binding by 70%, indicating that they were bound to the same receptor. Prorenin or renin binding was calculated as the difference between total binding and the binding in the presence of an excess of nonradioactive compound. The difference was adjusted as 100%. Preincubation of aliskiren or HRP was calculated in relation to untreated prorenin or renin.
Fluorescence-Activated Cell Sorter Analysis
U937 monocytes were incubated with rabbit purified IgG anti-(P)RR and the respective preimmune serum (generated by GN) with and without cell permeabilization. The Fix and Perm Cell Permeabilization kit (An-der-Grub) was used as described by the manufacturer. Corresponding fluorescein isothiocyanate (FITC) or phycoerythrin-labeled secondary antibodies were used for detection. For HRP binding, U937 cells were incubated with FITC-Ahx-RIFLKRMPSI-COOH (10–6 to 10–8 mol/L) without permeabilization for 15 minutes at 37°C. For competition experiments, U937 cells were preincubated with unlabeled HRP (10–7 mol/L) for 10 minutes, followed by a 15-minute incubation with FITC-HRP (10–8 mol/L). We also incubated embryonic stem cells RST307 (BayGenomics), which have a gene trap for the (P)RR and, therefore, lack the transmembrane domain of the (P)RR with FITC-HRP (10–7 mol/L). Stained cells were analyzed in a BD FACScan Flow Cytometer (Becton Dickinson).
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Results |
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We first investigated freshly isolated human monocytes, U937 cells, and a microsomal preparation of U937 cells in terms of (P)RR mRNA expression (Figure 1A). All 3 of the cell samples showed an abundant (P)RR mRNA expression. We next performed fluorescence-activated cell sorter analysis for (P)RR. (P)RR protein expression was present in permeabilized human monocytes (Figure 1B). We also detected a modest (P)RR protein expression on the surface of U937 cells without permeabilization (Figure 1C) and a higher expression in permeabilized U937 cell (Figure 1D).
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We subsequently focused on renin-induced ERK 1/2 signaling. To exclude any Ang II-mediated signaling effect, we performed our renin and prorenin signaling experiments in the presence of the AT1 blocker losartan and the AT2 blocker PD123319. Time course analysis revealed that human recombinant renin induced ERK 1/2 phosphorylation in a time-dependent manner starting at 15 minutes with a long-lasting signal up to 60 minutes (Figure 2A; quantification of the phospho-ERK 1/2 signal is shown in supplement Figure S1A, available at http://hyper.ahajournals.org). P42/44 MAPK activity measurements confirmed these results (Figure 2B). We then addressed the question of whether renin-ERK signaling is mediated via the activation of the epidermal growth factor (EGF) receptor. In contrast to Ang II-induced EGF receptor phosphorylation in smooth muscle cells (vascular smooth muscle cells), we found no evidence that renin induced EGF receptor phosphorylation in U937 cells (Figure 2C, middle). EGF receptor Western blot demonstrated equal loading (Figure 2C, bottom). Renin-stimulated extracts from the same samples showed increased phospho-ERK (Figure 2C, top). In addition, the EGF receptor blocker AG1478 also did not prevent renin-mediated phospho-ERK (data not shown). To address a potential role of PKC /β, we pretreated our U937 cells with Gö6976. However, Gö6976 did not prevent renin-induced ERK 1/2 activation (Figure 2D). In contrast, MEK 1/2 inhibitor PD98059 significantly reduced renin-mediated ERK 1/2 phosphorylation by 51±15% (P<0.05 versus renin-stimulated U937; Figure 2E). The ubiquitous mannose-6-phosphate receptor was shown to play a role in renin and prorenin binding, internalization, and degradation in neonatal rat cardiomyocytes.14 Therefore, to test the notion that the mannose-6-phosphate receptor is involved in renin-induced ERK 1/2 phosphorylation in U937 cells, we also analyzed deglycosylated renin. We found that renin without sugar side chains activates ERK 1/2 in a similar fashion compared with glycosylated renin, indicating that the mannose-6-phosphate receptor is not responsible for the signaling (Figure 2F; quantification of the phospho-ERK 1/2 signal is shown in Figure S1B).
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Because our results indicate that the (P)RR binds renin, as well as prorenin, we analyzed prorenin-induced ERK 1/2 signaling. Similarly to renin, prorenin induced phospho-ERK from 30 to 45 minutes (Figure 3A; quantification of the phospho-ERK 1/2 signal is shown in supplement Figure S1C). Prorenin-induced ERK 1/2 activation (Figure 3B, top) is also not mediated via the EGF receptor, because prorenin could not induce EGF receptor phosphorylation (Figure 3B, middle). Consistent with renin signaling, prorenin-induced phospho-ERK could not be blocked by the PKC /β inhibitor Gö6976 (Figure 3C) but was reduced by 32±3% (P<0.05 versus prorenin-treated U937) with the MEK 1/2 inhibitor PD98059 (Figure 3D).
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Whether aliskiren might also interfere with renin or prorenin (P)RR signaling was unknown. Aliskiren preincubation with renin slightly increased renin-induced phospho-ERK 1/2x18±5% (P<0.05 versus renin-treated U937; Figure 4A). Aliskiren did not affect renin-induced p42/44 MAPK activity (Figure 4B). In agreement with this finding, aliskiren did not alter prorenin-induced signaling (3±8% increase in phospho-ERK1/2 versus prorenin alone; P value not significant; Figure 4C). We next investigated the effect of the alleged competitive (P)RR blocker HRP. Fluorescence-activated cell sorter analysis from U937 cells showed that FITC-HRP was bound in a dose-dependent manner (Figure 5A). Competition experiments with a 10-fold excess of unlabeled HRP demonstrated that FITC-HRP could be partially displaced (Figure 5B). We then analyzed embryonic stem cells with a gene trap for the (P)RR. These cells lack the transmembrane domain of the (P)RR and should, therefore, not bind FITC-HRP. To our surprise, we found that FITC-HRP showed a clear-cut rightward shift indicating HRP binding (Figure 5C). Furthermore, HRP pretreatment slightly enhanced renin-induced ERK 1/2 phosphorylation by 15±3% (P<0.05 versus renin-treated U937). In contrast, prorenin-induced ERK 1/2 phosphorylation was not significantly affected by HRP (
9±4%; P value not significant; Figure 5D and 5E, respectively). Additional evidence that neither aliskiren nor HRP was able to inhibit renin and prorenin signaling comes from our binding studies. 125I-renin (Figure 6A) and 125I-prorenin (Figure 6B) binding in U937 cells were not influenced by aliskiren or by HRP.
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Discussion |
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We found that both prorenin and renin induce rapid cellular signals, which lead to MAPK ERK 1/2 phosphorylation, independent of Ang II. Prorenin- and renin-induced ERK 1/2 phosphorylation did not require PKC-
/β or the EGF receptor. In contrast, a MEK-1/2 inhibitor inhibited prorenin- and renin-induced ERK 1/2 activation. Aliskiren affected neither prorenin and renin binding to U937 cells nor ERK 1/2 activation. We conclude that aliskiren is a pure active renin inhibitor and has no (P)RR blocking action. We found no evidence of a specific blockade of the (P)RR by the HRP. Despite its putative in vivo potency in experimental diabetic nephropathy,5,9 the HRP was ineffective in preventing prorenin and renin binding to U937 cells, as well as prorenin- and renin-induced ERK1/2 signaling. Our signaling results are in agreement with a recent in vivo study from our group in renovascular hypertensive Goldblatt rats. The rats developed high renin, prorenin, and plasma renin activity (PRA), leading to Ang II-dependent target organ damage. However, chronic HRP treatment did not improve target organ damage.16 These results and the binding of HRP in embryonic stem cells that lack the transmembrane domain of the (P)RR challenge the concept that HRP acts as a specific (P)RR antagonist. Ang-converting enzyme inhibitors, AT1 receptor blockers, and direct renin inhibitors all increase renin concentration, which could conceivably induce (P)RR signaling independent of Ang II. We know that the (P)RR acts as a (pro)renin cofactor on the cell surface. (P)RR binding unmasks prorenin catalytic activity and thereby increases the efficiency of angiotensinogen cleavage by renin.3,17 Furthermore, the receptor induces Ang II-independent cellular effects in renal mesangial cells.3,10,11 This state of affairs strongly suggests that blockade of the (P)RR might be an alternative or an adjunct to renin-Ang system inhibition, particularly in conditions with high renin and/or prorenin levels.
Luetscher and colleagues18,19 reported that an inactive form of renin, prorenin, was present in the plasma of diabetic patients with target organ damage at a much higher level compared with healthy humans. High prorenin levels, and not PRA, were closely associated with the severity of diabetic complications in these patients. Diabetic patients generally have rather low circulating plasma renin activity. How prorenin activation might occur in vivo was time unclear at that. Before the discovery of the (P)RR, acid activation and cryoactivation of prorenin, in addition to proteolytic activation with trypsin and other enzymes, were well known. However, these mechanisms did not seem to be physiologically relevant, because neither acid activation nor cryoactivation can occur within the body.18,20–22
The (P)RR now offers a more (patho)physiological activation mechanism with additional novel functions. Our results are the first to show that prorenin, in addition to renin, induces Ang II-independent direct ERK 1/2 MAPK activation. These results are in agreement with those of Huang et al,10,11 who showed that renin signaling via the (P)RR activates ERK 1/2, transforming growth factor-β, as well as profibrotic molecules collagen and fibronectin. Saris et al23 reported that prorenin induced p38 MAPK but not ERK 1/2 signaling in rat neonatal cardiomyocytes. Altogether, it is tempting to speculate that high prorenin, as is seen in diabetic patients, might interact with the (P)RR and, thus, contributes to the pathogenesis of target-organ damage.
High PRA is regarded as a risk factor for myocardial infarction in untreated hypertensive and normotensive patients.24,25 The recent clinical availability of aliskiren allows for direct renin inhibition and reduces PRA. In contrast, other inhibitors of the renin-Ang system increase PRA. Aliskiren lowered blood pressure in mild to moderately hypertensive patients26,27 and demonstrated target-organ protection in a hypertensive double transgenic rat model expressing human genes for renin and angiotensinogen.1,2,28 Whether aliskiren might also block renin or prorenin (P)RR signaling was unknown. Our data clearly speak against such an effect, because renin and/or prorenin preincubated with aliskiren did not reduce binding and MAPK activation. Nonetheless, aliskiren could still block the tissue renin-Ang system, because activated prorenin would immediately be occupied by aliskiren so that local Ang II generation could not occur. The fact that Ang-converting enzyme inhibitors and AT1 receptor blockers proved highly effective in reducing target-organ damage in diabetic patients in spite of their low PRA values has proved puzzling. One explanation could be the activation of prorenin by the (P)RR at the tissue level. Such activation would not be detected by circulating PRA measurements and could lead to local Ang II generation. The efficacy of aliskiren in terms of reducing target-organ damage in diabetic patients is currently the focus of a randomized, double-blind clinical trial.
The concept of (P)RR blockade is intriguing. Ichihara et al5 provided evidence that infusion of the presumed (P)RR blocker HRP ameliorated streptozotocin-induced diabetes and target organ damage in hypertensive rats. One unresolved issue is how prorenin and renin bind to (P)RR. Ichihara et al5 and Suzuki et al6 reported that the binding involves the handle region of the prosegment. Ostensibly, active renin, which does not possess the handle-region prosegment, should, therefore, not activate the (P)RR. One alternative explanation is that the renin has a binding site to the (P)RR within the lobes of the renin molecule. However, then the question arises as to how HRP could block this interaction. None of the studies by the Ichihara group5,7–9 actually demonstrated that HRP specifically inhibits renin binding in vitro. We showed here that FITC-tagged HRP binds to U937 monocytes. However, we found no evidence that HRP preincubation affected prorenin and renin binding in our cells or proof that HRP inhibited cell signaling. It is possible that HRP efficacy in vivo depends on an undefined mechanism but not on competitive antagonism for the (P)RR.
Ang II signaling also leads to ERK 1/2 phosphorylation.29 We excluded any potential renin- or prorenin-induced Ang II-mediated signaling effects in our study. We performed our experiments in the presence of the AT1 and AT2 receptor blockers, as well as with aliskiren. Nevertheless, the most convincing evidence for a distinct signaling mechanism derives from our prorenin and renin signaling analysis. Although canonical Ang II-mediated ERK 1/2 activation depends on the transactivation of the EGF receptor,29 we found no evidence that prorenin or renin signaling phosphorylated the EGF receptor. Furthermore, the EGF receptor blocker AG1478 had no effect. Therefore, we believe that prorenin- and renin-induced ERK1/2 activation are mediated by a signaling pathway different from that of Ang II. Interestingly, Schefe et al30 found that, on renin stimulation, the (P)RR is able to dimerize and induces the transcription factor promyelocytic zinc finger protein. Promyelocytic zinc finger then leads to downregulation of the (P)RR. Promyelocytic zinc finger is also involved in Ang II AT2 receptor signaling.31 Whether prorenin/renin signaling provides for cross-talk to Ang II-AT2 receptor signaling needs to be further defined.
We are aware of limitations in our study. We used monocytes and the U937 cell line as a system to evaluate signaling of renin and prorenin, as well as the effect of potential (P)RR blockers, although our focus was not specifically on the signaling effect in monocytes. Our most provocative findings are those that are negative, namely, that we could not find a blocking effect on (P)RR by HRP in our signaling experiments. The same was true in vivo in the renovascular hypertensive Goldblatt model.16 Nonetheless, we believe our findings are fundamental. For instance our study provides the first evidence that prorenin, in addition to renin, mediates direct ERK 1/2 signaling independent of Ang II. Finally, we hasten to add that our observations "stacked the deck" in favor of renin, as opposed to prorenin. Our animal-related study is a high-renin model rather than a prorenin model.16 Our binding studies suggest that the HRP may bind elsewhere as well. We regard these findings as exciting. Because Batenburg et al32 have recently designated prorenin as the primary endogenous ligand of the (P)RR, we are challenged to address more appropriate models. Previous work will guide us in this direction.5,18,19
Perspectives
The implications of our investigation extend beyond cardiovascular disease. For instance, Ramser et al33 found that patients with a mutation in the (P)RR gene develop epilepsy with mental retardation. Interestingly, similar findings have been described in persons who lack or have mutations in the Ang II AT2 receptor.34 Our studies will hopefully draw further attention to the (P)RR as a pharmacological target and lead to additional, more effective, compounds.
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Acknowledgments |
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We thank Petra Quass, May-Britt Köhler, Gabriele N'diaye, Mathilde Schmidt, and Jana Czychi for their excellent technical assistance.
Sources of Funding
The European Union (EuReGene), the Dutch Heart Foundation (NHS2005.B096) and the Novartis Foundation (Nürnberg, Germany) supported the studies. D.N.M. is a Helmholtz research fellow. The Deutsche Forschungsgemeinschaft supported A.F., D.N.M., and F.C.L. M.B., G.N., A.H.J.D., D.N.M., and F.C.L. received a grant-in-aid from Novartis to study aliskiren.
Disclosures
F.C.L., G.N., A.H.J.D., and D.N.M. serve as advisors for Novartis. The remaining authors report no conflicts.
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Footnotes |
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The first 3 authors contributed equally to this work.
Received September 18, 2007; first decision October 5, 2007; accepted December 17, 2007.
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