(Hypertension. 1997;30:1389-1396.)
© 1997 American Heart Association, Inc.
Articles |
Mannose 6-Phosphate Receptor–Mediated Internalization and Activation of Prorenin by Cardiac Cells
From the Cardiovascular Research Institute COEUR, Departments of Pharmacology (C.A.M. van K., A.H.J.D., P.R.S), Biochemistry (D.H.W.D., J.M.J.L.), and Internal Medicine I (C.A.M. van K., F.H.M.D., M.A.D.H.S.), Erasmus University Rotterdam, Rotterdam, The Netherlands.
Correspondence to A.H.J. Danser, PhD, Department of Pharmacology, Room EE1418b, Erasmus University, Dr. Molewaterplein 50, 3015 GE Rotterdam, Netherlands. E-mail danser{at}farma.fgg.eur.nl
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract The binding and internalization of recombinant human renin and prorenin (2500 µU/mL) and the activation of prorenin were studied in neonatal rat cardiac myocytes and fibroblasts cultured in a chemically defined medium. Surface-bound and internalized enzymes were distinguished by the addition of mannose 6-phosphate to the medium, by incubating the cells both at 37°C and 4°C, and by the acid-wash method. Mannose 6-phosphate inhibited the binding of renin and prorenin to the myocyte cell surface in a dose-dependent manner. At 37°C, after incubation at 4°C for 2 hours, 60% to 70% of cell surface-bound renin or prorenin was internalized within 5 minutes. Intracellular prorenin was activated, but extracellular prorenin was not. The half-time of activation at 37°C was 25 minutes. Ammonium chloride and monensin, which interfere with the normal trafficking and recycling of internalized receptors and ligands, inhibited the activation of prorenin. Results obtained with cardiac fibroblasts were comparable to those in the myocytes. This study is the first to show experimental evidence for the internalization and activation of prorenin in extrarenal cells by a mannose 6-phosphate receptor–dependent process. Our findings may have physiological significance in light of recent experimental data indicating that angiotensin I and II are produced at cardiac and other extrarenal tissue sites by the action of renal renin and that intracellular angiotensin II can elicit important physiological responses.
Key Words: endocytosis • fibroblasts • myocytes • heart • renin
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
A local renin-angiotensin system in the heart is often invoked to explain the long-term beneficial effects of angiotensin-converting enzyme inhibitor treatment on postinfarction cardiac remodeling and failure and in left ventricular hypertrophy.
Experimental studies of the isolated perfused rat heart have indeed demonstrated that the heart is capable of producing Ang I and Ang II.1 2 However, attempts to provide evidence that the cardiac production of these peptides depends on in situ synthesized renin have failed so far. Rather, perfusion experiments in the isolated rat heart, as well as studies of the effects of nephrectomy on the cardiac tissue levels of Ang I and II in the pig, indicate that the local production of these peptides depends on kidney-derived renin.1 2 3
Uptake of renin from the circulation by vascular tissues and by the heart has been reported and appears to contribute to blood pressure control.3 4 5 Binding of rat renin to rat cardiac and other tissue membranes has also been reported, as has binding of human renin to human umbilical vein endothelial cells.6 7 8 A recent study has demonstrated specific receptor binding of human renin to cultured human mesangial cells.9
Recombinant human renin synthesized by Xenopus oocytes and mouse L cells contains phosphomannosyl residues that are recognized by specific receptors (mannose 6-phosphate receptors), as does human prorenin synthesized by CHO cells.10 11 Two different mannose 6-phosphate receptors have been identified; one is dependent on divalent cations, the other not. Both mannose 6-phosphate receptors function in the process of intracellular lysosomal enzyme sorting, and the cation-independent receptor is also capable of binding and internalizing extracellular lysosomal enzymes.12 13
The aim of the present study was to explore the possibility that cardiac myocytes and fibroblasts are capable of binding and internalizing renin and prorenin and that these processes are mannose 6-phosphate receptor–mediated. We also addressed the possibility that receptor-mediated endocytosis of prorenin results in its activation.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Reagents
Trypsin (type III), bovine serum albumin, monensin, mannose 6-phosphate, mannose 1-phosphate, and glucose 6-phosphate were from Sigma Chemical Co. Fetal calf serum, horse serum, penicillin, and streptomycin were purchased from Boehringer-Mannheim. DMEM and Medium 199 were from Gibco, Life Technologies. Six-well tissue plates were obtained from Costar.
Cell Culture
All experiments were performed according to the regulations of
the Animal Care Committee of Erasmus University, Rotterdam,
Netherlands, in accordance with the Guiding Principles in the
Care and Use of Animals approved by the American
Physiological Society.
Primary cultures of neonatal rat ventricular cardiomyocytes and fibroblasts were prepared as described before.14 Briefly, ventricles from newborn 1- to 3-day-old Wistar rats were minced, and cells were isolated in eight subsequent trypsinization steps at 30°C. Noncardiomyocytes were separated from the cardiomyocytes by differential preplating. Cardiomyocytes were seeded in 6-well plates at 1.5x106 cells per well, giving a confluent monolayer of spontaneously beating cells after 24 hours. The preplated cells (fibroblast fraction) were passaged after 4 days to 6-well dishes at 0.75x106 cells per well. The cells were maintained in a humidified incubator at 37°C and 5% CO2 in air, in growth medium consisting of DMEM and Medium 199 (4:1, vol/vol), supplemented with 5% fetal calf serum, 5% horse serum, 100 U penicillin/mL, and 100 µg streptomycin/mL for 72 hours. The incubations with renin and prorenin (see below) were carried out under serum-free conditions. Before the start of each experiment, cells were washed with 3 mL warm (37°C) PBS (140 mmol/L NaCl, 2.6 mmol/L KCl, 1.4 mmol/L KH2PO4, 8.1 mmol/L Na2HPO4, pH 7.4). The cells were then preincubated either at 37°C or 4°C for 30 minutes with 0.9 mL incubation medium consisting of DMEM and Medium 199 (4:1, vol/vol), supplemented with 1% (wt/vol) bovine serum albumin.
Prorenin and Renin
Recombinant human prorenin was a kind gift of Dr W. Fischli
(Hoffmann-LaRoche, Basel, Switzerland). It was produced in CHO cells
transfected with a vector containing human prorenin cDNA. It was
partially purified to remove traces of renin by Cibacron Blue Sepharose
affinity chromatography.15 The intrinsic
renin activity of the prorenin preparation, prior to proteolytic
activation, was <2% of the activity after complete proteolytic
activation. After proteolytic activation, the prorenin preparation
contained approximately 8.5x106 µU/mL renin. Recombinant
human renin was prepared by the proteolytic activation of the
recombinant human prorenin with immobilized
trypsin.3 15 Sepharose-bound trypsin (final concentration,
0.25 mg trypsin/mL) was added to the prorenin preparation, and the
mixture was kept at 4°C for 72 hours. Trypsin was then removed by
centrifugation. The prorenin and renin preparations
were stored at -70°C.
Incubation of Cells With Renin or Prorenin at 37°C or
4°C
After preincubation at 37°C or 4°C for 30 minutes in 0.9 mL
serum-free medium (see above), experiments were started by the addition
of 0.1 mL of a dilution of recombinant human renin or prorenin to the
medium (final concentration in the wells was approximately 2500
µU/mL). Cells were then incubated at 37°C or 4°C. Incubations
were also performed in the presence of mannose 6-phosphate (0.01
µmol/mL to 50 µmol/mL), mannose 1-phosphate (1µmol/mL),
glucose 6-phosphate (1 µmol/mL), ammonium chloride (50
µmol/mL), or monensin (0.01 µmol/mL).
At the end of the incubation period, the culture medium was removed and quickly frozen on dry ice. Each well was washed three times with 3 mL ice-cold PBS. Renin and prorenin were not detectable in the last PBS wash. Cells were then lysed in 0.5 mL ice-cold PBS containing 0.2% Triton X-100, and the cell lysates were quickly frozen on dry ice. Medium and cell lysate were stored at -70°C until assayed for renin and prorenin.
To determine the internalized renin or prorenin, the acid-wash method was used.16 Briefly, after the cells had been washed three times with 3 mL ice-cold PBS, the cells were incubated at 4°C with 1 mL of an acid solution containing 50 mmol/L glycine and 150 mmol/L NaCl, pH 3.0. After 10 minutes the acid solution was removed, and the cells were washed three times with 3 mL ice-cold PBS. Cells were then lysed in 0.5 mL ice-cold PBS containing 0.2% Triton X-100, as described above.
To determine the prorenin that was bound to mannose 6-phosphate receptors on the cell surface, prorenin was measured in the culture medium before and after its displacement from the receptor by mannose 6-phosphate. For this purpose, the cells were preincubated at 37°C or 4°C with prorenin (2500 µU/mL) for 2 hours. The cells were then washed three times with 3 mL ice-cold PBS. After the last wash, 1 mL of fresh incubation medium, free of serum and renin and prorenin, containing mannose 6-phosphate (final concentration, 10 µmol/mL) was added, and the incubations were continued at the same temperature as during the preincubation. After this second incubation period, the cells were washed and lysed as described above.
Incubation of Cells at 4°C Followed by Incubation at
37°C
To study the kinetics of renin and prorenin internalization and
prorenin activation in more detail, cells were incubated with renin or
prorenin (final concentration, approximately 2500 µU/mL) for 2 hours
at 4°C. After this period, free renin and prorenin were removed by
washing the cells three times with 3 mL ice-cold PBS. After the last
wash, 1 mL of fresh incubation medium at 37°C without renin and
prorenin was added, and the cells were incubated at 37°C. The
incubations were terminated by washing the cells with ice-cold PBS. The
cells were then lysed as described above. Medium and cell lysate were
assayed for renin and prorenin. Internalized renin and prorenin were
determined with the acid-wash method as described above.
Renin and Prorenin Measurements
Measurements of renin were made with the enzyme-kinetic
assay.3 15 Briefly, 100 µL sample was incubated for 3
hours with saturating amounts of sheep renin substrate at 37°C and pH
7.4 in the presence of serine protease and angiotensinase
inhibitors. The generated Ang I was quantified by
radioimmunoassay. Results were expressed as µU/mL using the
international World Health Organization human kidney renin standard,
lot 68/356 (WHO International Laboratory for Biological Standards and
Control, Potter Bar, Hertfordshire, UK), as a reference. The Ang
I–generating activity we measured in cells that had been exposed to
renin in the culture medium represents "true" renin; the
specific inhibitor remikiren,17 at a
concentration of 10-8 mol/mL, caused complete inhibition
of the Ang I–generating activity of the lysates from these cells.
Prorenin is the inactive biosynthetic precursor of renin. The prorenin-to-renin conversion in vivo is a proteolytic process by which the propeptide is cleaved from the renin part of the molecule. In vitro, prorenin can be activated both nonproteolytically (eg, by exposure to low pH) and proteolytically by various enzymes. The Ang I–generating activity we measured in the lysates of cells that had been exposed to inactive prorenin in the culture medium represents prorenin that was activated by the cells. This cell-activated prorenin may or may not be identical with renin. We also measured "total" prorenin, ie, prorenin that was activated by the cells plus prorenin that was not activated by the cells. For these measurements, the samples were incubated for 48 hours at 4°C with plasmin (0.5 casein units/mL) before the incubation with sheep renin substrate.3 The preincubation with plasmin caused complete proteolytic activation of prorenin. Plasmin from the activation step was inactivated by the serine protease inhibitor aprotinin (final concentration, 100 kallikrein-inhibiting units/mL) that had been added to the incubation medium of the Ang I–generating step.
Prorenin that could be measured without preincubation of the samples with plasmin is referred to as "cell-activated" prorenin. Prorenin that was measured in samples that had been preincubated with plasmin is referred to as "total" prorenin. Mannose 6-phosphate, ammonium chloride, and monensin in the concentrations we used had no influence on the renin and prorenin assays.
Statistics
Data were compared using Student's t test for
unpaired observations. A value of P<.05 was considered to
be significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Figs 1
(top) and
2 (top) show the amounts of
cell-associated renin and prorenin after 4 hours of incubation of
cardiac myocytes at either 4°C or 37°C with renin or prorenin,
respectively. At 4°C the cells bound both renin and prorenin, but
internalization occurred only at 37°C. The cell-associated renin or
prorenin after 4 hours of incubation amounted to about 5% of the total
quantity in the culture medium both at 4°C and 37°C. After
incubation at 37°C, most of the cell-associated prorenin was
resistant to the acid-wash and was in an activated
form, whereas at 4°C prorenin was washed away by acid and remained
inactive.
|
Fig 3 shows the increase in
cell-associated prorenin over time in the myocytes at 37°C.
Cell-associated prorenin reached a maximum in 3 to 4 hours. It was
120±37 µU/1.5x106 cells (mean±SD, n=9) at 4 hours of
incubation, and more than 90% was in an activated form at that
time. When at 2 hours of incubation at 37°C, the prorenin-containing
medium was renewed and the cells were incubated for another 2 hours at
37°C, the cell-associated prorenin rose to levels well above the
maximum obtained without renewal of the medium, and again more than
90% was in an activated form. The cell-associated prorenin at
4 hours of incubation, 2 hours after renewal of the medium, was
160±41% of the level at 4 hours of incubation without renewal of the
medium (n=5, P<.05 for difference from 100%).
|
When the incubations at 37°C were carried out in the presence of
mannose 6-phosphate (10 µmol/mL), cell-associated prorenin at 4
hours of incubation was 24±8 µU/1.5x106 cells (n=5,
P<.01 for difference from incubations in the absence of
mannose 6-phosphate). Fig 4 shows the
effect of different concentrations of mannose 6-phosphate on the levels
of cell-associated prorenin at 37°C and 4°C; 50% inhibition was
reached at a mannose 6-phosphate concentration in the order of 0.1
µmol/mL. Mannose 1-phosphate (n=3) and glucose 6-phosphate (n=3) at a
concentration of 1 µmol/mL were without effect (data not
shown).
|
Fig 5 shows the effect of mannose
6-phosphate on myocytes that had been incubated for 2 hours with
prorenin at either 4°C or 37°C. After incubation with prorenin, the
cells were washed with ice-cold PBS and incubated at 4°C or 37°C,
respectively, for 2 hours in serum-free medium to which mannose
6-phosphate (final concentration, 10 µmol/mL) but not prorenin
had been added. After preincubation with prorenin at 4°C, mannose
6-phosphate displaced the cell-associated prorenin into the medium. No
displacement by mannose 6-phosphate was observed after preincubation
with prorenin at 37°C. Mannose 6-phosphate had similar effects after
preincubation with renin (data not shown). These observations are in
agreement with the results obtained with the acid-wash method. The two
sets of results indicate that at 4°C the cell-associated renin and
prorenin remain surface-bound, whereas at 37°C most of it appears to
be internalized.
|
The marked reduction in cell-associated prorenin in response to mannose
6-phosphate was not seen when instead of mannose 6-phosphate, ammonium
chloride (50 µmol/mL) or monensin (0.01 µmol/mL) had been
added to the medium (Fig 6). Both
ammonium chloride and monensin, however, inhibited the cellular
activation of prorenin. In the control incubations, the fraction of
cell-associated prorenin that was in an activated form rose
from 30% after 30 minutes to 90% after 4 hours. This was reduced to
10% and 35%, respectively, by ammonium chloride and to 5% and 10%
by monensin (Fig 7, left panel).
|
|
Fig 8 and Fig 9 show the results of experiments in
which the myocytes were preincubated with either renin or prorenin at
4°C for 2 hours and then incubated at 37°C without renin or
prorenin. At 37°C, after the incubation at 4°C, approximately 70%
of cell surface-bound renin and 60% of cell surface-bound prorenin
were internalized within 5 minutes, and most of the remainder was
released into the medium. Results for renin and prorenin were not
significantly different. Intracellular prorenin was activated,
but most, if not all, extracellular prorenin remained inactive. The
half-time of intracellular prorenin activation was approximately 25
minutes. There was no evidence that prorenin, once internalized, was
released by the cells back into the medium.
|
|
Experiments identical to those performed in the cardiac myocytes, as
shown in Fig 1
(top), Fig 2 (top), and Fig 7 (left), were carried out
with the use of cardiac fibroblasts. Results of the two sets of
experiments were very similar (Fig 1, bottom; Fig 2, bottom; and Fig 7, right). The kinetics of internalization and activation of prorenin by
cardiac fibroblasts at 37°C, after preincubation at 4°C for 2
hours, were also similar to those observed in the myocytes (results not
shown). At 37°C, after the incubation at 4°C, 42±19% of the cell
surface-bound prorenin was internalized within 5 minutes (n=5), and the
half-time of intracellular prorenin activation was approximately 25
minutes, as it was in the myocytes. Release of internalized prorenin
from the fibroblasts back into the culture medium could not be
detected, which also corresponds with our observations in the myocytes.
As in the myocytes, the binding of renin and prorenin to the
fibroblasts was inhibited by mannose 6-phosphate.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study indicates that renin and prorenin are internalized by cardiac myocytes and fibroblasts and that prorenin, after its internalization, is rapidly activated. At 4°C both renin and prorenin bound to the cell surface, and at 37°C both were rapidly internalized. It appears therefore that neither the catalytic domain of the enzyme nor the propeptide domain are essential for the processes of binding and internalization. There was no indication that renin and prorenin, once internalized, were released into the culture medium. The acid-wash method that we used to distinguish between surface-bound and internalized renin or prorenin has been validated for a number of peptide hormone receptors and their ligands, including lysosomal enzymes carrying the mannose 6-phosphate signal. Exposure to low pH causes rapid dissociation of these enzymes from cell-surface mannose 6-phosphate receptors.12 To check whether the acid-wash method is also applicable to the cell binding of prorenin, the cells were incubated with prorenin at 4°C. At this low temperature, the internalization process is known to be effectively inhibited. We found that after incubation with prorenin for 2 hours, the cell-associated prorenin was completely removed from the cells by the acid-wash. In contrast, when, after incubation with prorenin at 4°C, the cells were incubated at 37°C with fresh medium without prorenin, nearly all cell-associated prorenin became resistant to the acid-wash within 5 minutes (the first measurement point). Thus, it appears that the acid treatment of the cells did not affect the nonsurface-bound, ie, internalized, prorenin. The cell-surface binding of renin and prorenin at 4°C and its internalization at 37°C were confirmed by our observations on the effects of mannose 6-phosphate. After incubation with prorenin for 2 hours at 4°C, the cell-associated prorenin could be displaced into the medium by the addition of mannose 6-phosphate to the medium, whereas no such displacement was observed after incubation with prorenin for 2 hours at 37°C. The results were similar when the cells were incubated with renin instead of prorenin.
Our results strongly suggest that the internalization is a mannose 6-phosphate receptor–dependent process. The inhibition of prorenin internalization by mannose 6-phosphate was specific and saturable, with an IC50 in the order of 0.1µmol/mL. This corresponds with other mannose 6-phosphate receptor–mediated responses.18 19 Our finding that most of the cell surface–bound renin and prorenin after preincubation with these enzymes at 4°C was internalized within 5 minutes of incubation at 37°C is also in agreement with published studies of other ligands that bind to cell-surface mannose 6-phosphate receptors via the mannose 6-phosphate signal.20
Approximately 5% of the renin or prorenin from the culture medium was bound and internalized by the cardiac cells. This low percentage may be related to the fact that only a small percentage of the renin and prorenin molecules carries the mannose 6-phosphate signal.11 21 That this, rather than the number of cell receptors, is the rate-limiting factor is also suggested by our experiments in which the prorenin-containing culture medium was renewed after 2 hours of incubation at 37°C, at a time when the amount of internalized prorenin was at 85% of its maximum. Renewal of the medium in these experiments caused a rise of intracellular prorenin to levels well above the maximum that was reached without renewal of the medium. These results have to be confirmed by binding studies, using radiolabeled prorenin.
The effects of mannose 6-phosphate that we observed were different from the inhibitory effects of ammonium chloride and monensin. Mannose 6-phosphate in the incubation experiments with prorenin at 37°C reduced the cellular concentrations of both total and cell-activated prorenin to equally low levels, whereas ammonium chloride and monensin had a much greater effect on the cellular level of cell-activated prorenin than on the cellular level of nonactivated prorenin. This supports the view that mannose 6-phosphate inhibits the binding of prorenin to cell-surface mannose 6-phosphate receptors, whereas ammonium chloride and monensin primarily act on events that follow the binding to these receptors. Ammonium chloride and monensin are known to interfere with the normal intracellular trafficking and the recycling and lysosomal degradation of internalized receptors and ligands.22
This study provides the first evidence of intracellular activation of prorenin, derived from the extracellular fluid, by extrarenal cells. The evidence in our study that a precursor protein is converted into a biologically active agent by a mannose 6-phosphate receptor–mediated and endocytosis-dependent process is not an isolated finding. It has been demonstrated for a number of precursor proteins, including the aspartyl protease cathepsin D.23 Cathepsin D is a lysosomal enzyme showing a high degree of structural homology with renin.24 Transforming growth factor-ß, which may modulate the growth-promoting actions of Ang II,25 is another example. This factor is produced in a latent form by vascular endothelial and smooth muscle cells and is converted into the active form in cocultures of these cells by a mannose 6-phosphate receptor–dependent process.19 The mannose 6-phosphate receptor that is involved in the endocytosis-dependent activation of both procathepsin and the latent form of transforming growth factor-ß is of the cation-independent type, which is identical with the insulin-like growth factor II receptor.19 23 It seems logical to assume that this is also the receptor that mediates the internalization and activation of prorenin which we observed in the present study.
Our findings may have physiological significance in light of the experiments by Swales' group (Thurston et al4 )in rats more than 15 years ago. Their experiments showed that the slow decrease in blood pressure after nephrectomy followed the same time course as the decrease in vascular renin and contrasted with the rapid decrease in circulating renin. In recent years, a series of perfusion studies using the isolated rat Langendorff heart and isolated rat hindquarters have provided direct evidence for the local production of Ang I and II.1 2 26 Angiotensin production in these studies was dependent on the presence of renin in the perfusion fluid.
Binding of renin to cell-surface receptors may not only be the first step in endocytosis of the renin-receptor complex but may also transduce other membrane-associated or intracellular events. Receptor-mediated binding of human renin to human renal mesangial cells in culture has been reported to cause an increase in [3H]thymidine incorporation and an increase in the concentration of plasminogen activator inhibitor-1 antigen in the conditioned medium.9 The concentration of renin at which these responses were observed was in the order of 100 000 fmol/mL. This is much higher than the concentration used in our experiments, which was 2500 µU/mL or approximately 50 fmol/mL. Even a concentration of 50 fmol/mL is very high; the normal concentrations of renin and prorenin in human plasma are approximately 0.5 fmol/mL and 5 fmol/mL, respectively.27 However, the lower in vivo concentrations may be sufficient because, in the in vivo situation, the cells are continuously exposed to prorenin carrying the mannose 6-phosphate signal, whereas in vitro this prorenin disappears from the culture medium because of uptake by the cells.
Cellular binding and internalization of renin and prorenin and intracellular activation of prorenin may lead to local levels of enzyme activity that are higher than those in the extracellular fluid. If angiotensinogen is internalized via bulk fluid endocytosis concurrently with the receptor-mediated endocytosis of renin and prorenin, a scenario is provided for intracellular Ang I generation. Ang II is known to stimulate plasminogen activator inhibitor-1 production by renal mesangial cells.28 The reported increase in plasminogen activator inhibitor-1 antigen in response to the binding of renin to these cells9 would therefore fit in the view that this is an Ang II–mediated effect. However, the question of whether Ang I and/or II are formed within the cells is highly controversial. It is possible that the reported responses of mesangial cells to the cellular binding of renin are independent of Ang I and II formation.
Our observations on the internalization of renin and prorenin and the intracellular activation of prorenin warrant further study addressing this issue. Internalized Ang II has a long half-life compared with circulating Ang II.29 It rapidly accumulates in cardiac and vascular muscle cell nuclei,30 where it may bind to chromatin and may influence transcriptional processes that are related to the growth-promoting effects of Ang II.31 Finally, recent experiments, in which Ang II was injected into cardiac myocytes and vascular smooth muscle cells, also favor the concept that intracellular Ang II may serve important functions.32 33 Studies addressing the possibility of intracellular angiotensin generation may therefore hold promise.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported by the Netherlands Heart Foundation, research grant 96.019.
Received May 5, 1997; first decision May 19, 1997; accepted July 9, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lindpaintner K, Jin M, Niedermaier N, Wilhelm MJ, Ganten D. Cardiac angiotensinogen and its local activation in the isolated perfused beating heart. Circ Res. 1990;67:564–573.
2.
de Lannoy LM, Danser AHJ, van Kats JP, Schoemaker RG,
Saxena PR, Schalekamp MADH. Renin-angiotensin system
components in the interstitial fluid of the isolated
perfused rat heart: local production of angiotensin
I. Hypertension. 1997;29:1240–1251.
3.
Danser AHJ, van Kats JP, Admiraal PJJ, Derkx FHM,
Lamers JMJ, Verdouw PD, Saxena PR, Schalekamp MADH. Cardiac renin and
angiotensins: uptake from plasma versus in situ synthesis.
Hypertension. 1994;24:37–48.
4.
Thurston H, Swales JD, Bing RF, Hurst BC, Marks ES.
Vascular renin-like activity and blood pressure maintenance in
the rat: studies on the effect of changes in sodium balance,
hypertension, and nephrectomy. Hypertension. 1979;1:643–649.
5. van Kats JP, Sassen LMA, Danser AHJ, Polak MPJ, Soei LK, Derkx FHM, Schalekamp MADH, Verdouw PD. Assessment of the role of the renin-angiotensin system in cardiac contractility utilizing the renin inhibitor remikiren. Br J Pharmacol. 1996;117:891–901.[Medline] [Order article via Infotrieve]
6. Sealey JE, Catanzaro DF, Lavin TN, Gahnem F, Pittaresi T, Hu L-F, Laragh JH. Specific prorenin/renin binding (ProBP): identification and characterization of a novel membrane site. Am J Hypertens. 1996;9:491–502.[Medline] [Order article via Infotrieve]
7. Campbell DJ, Valentijn AJ. Identification of vascular renin-binding proteins by chemical cross-linking: inhibition of binding of renin by renin inhibitors. J Hypertens. 1994;12:879–890.[Medline] [Order article via Infotrieve]
8. Admiraal PJJ, Sluiter W, Derkx FHM, Schalekamp MADH. Uptake and intracellular activation of prorenin in human endothelial cells. Am J Hypertens. 1995;8:42A. Abstract.
9. Nguyen G, Delarue F, Berrou J, Rondeau E, Sraer J-D. Specific binding of renin to human mesangial cells in culture increases plasminogen activator-1 antigen. Kidney Int. 1996;50:1897–1903.[Medline] [Order article via Infotrieve]
10. Nakayama K, Hatsuzawa K, Kim W-S, Hashiba K, Yoshino T, Hori H, Murakami K. The influence of glycosylation on the fate of renin expressed in Xenopus oocytes. Eur J Biochem. 1990;191:281–285.[Medline] [Order article via Infotrieve]
11. Aeed PA, Guido DM, Mathews WR, Elhammer ÅP. Characterization of the oligosaccharide structures on recombinant human prorenin expressed in Chinese hamster ovary cells. Biochemistry. 1992;31:6951–6961.[Medline] [Order article via Infotrieve]
12. Dahms NM, Lobel P, Kornfeld S. Mannose 6-phosphate receptors and lysosomal enzyme targeting. J Biol Chem. 1989;264: 12115–12118.
13. Kornfeld S. Structure and function of the mannose 6-phosphate/insulin-like growth factor II receptors. Ann Rev Biochem. 1992;61:307–330.[Medline] [Order article via Infotrieve]
14. van Heugten HAA, Bezstarosti K, Dekkers DHW, Lamers JMJ. Homologous desensitization of the endothelin-1 receptor mediated phosphoinositide response in cultured neonatal rat cardiomyocytes. J Mol Cell Cardiol. 1993;25:41–52.[Medline] [Order article via Infotrieve]
15.
Derkx FHM, Schalekamp MPA, Schalekamp MADH.
Prorenin-renin conversion: isolation of an intermediary form of
activated prorenin. J Biol Chem. 1987;262:2472–2477.
16.
Ascoli M. Internalization and degradation of
receptor-bound human choriogonadotropin in Leydig tumor cells.
J Biol Chem. 1982;257:13306–13311.
17.
Fischli W, Clozel JP, Amrani KE, Wostl W, Neidhart W,
Stadler H, Branca Q. Ro 42–5892 is a potent orally active renin
inhibitor in primates. Hypertension. 1991;18:22–31.
18. Brauker JH, Roff CF, Wang JL. The effect of mannose 6-phosphate on the turnover of the proteoglycans in the extracellular matrix of human fibroblasts. Exp Cell Res. 1986;164:115–126.[Medline] [Order article via Infotrieve]
19.
Dennis PA, Rifkin DB. Cellular activation of latent
transforming growth factor ß requires binding to the
cation-independent mannose 6-phosphate/insulin-like growth factor type
II receptor. Proc Natl Acad Sci U S A.. 1991;88:580–584.
20.
Green SA, Kelly RB. Low density lipoprotein receptor
and cation-independent mannose 6-phosphate receptor are transported
from the cell surface to the Golgi apparatus at equal rates
in PC12 cells. J Cell Biol. 1992;117:47–55.
21.
Faust PL, Chirgwin JM, Kornfeld S. Renin, a
secretory glycoprotein, acquires phosphomannosyl residues.
J Cell Biol. 1987;105:1947–1955.
22. Wileman T, Harding C, Stahl P. Receptor-mediated endocytosis. Biochem J. 1985;232:1–14.[Medline] [Order article via Infotrieve]
23.
Helseth DL, Veis A. Cathepsin D-mediated processing of
procollagen: lysosomal enzyme involvement in secretory processing of
procollagen. Proc Natl Acad Sci U S A.. 1984;81:3302–3306.
24.
Faust PL, Kornfeld S, Chirgwin JM. Cloning and sequence
analysis of cDNA for human cathepsin D. Proc Natl Acad
Sci U S A.. 1985;82:4910–4914.
25.
Koibuchi Y, Lee WS, Gibbons GH, Pratt RE. Role of
transforming growth factor-ß1 in the cellular growth response to
angiotensin II. Hypertension. 1993;21:1046–1050.
26. Hilgers KF, Kuczera M, Wilhelm MJ, Wiecek A, Ritz E, Ganten D, Mann JFE. Angiotensin formation in the isolated rat hindlimb. J Hypertens. 1989;7:789–798.[Medline] [Order article via Infotrieve]
27.
Derkx FHM, de Bruin RJA, van Gool JMG, van den Hoek
M-J, Beerendonck CCM, Rosmalen F, Haima P, Schalekamp MADH. Clinical
validation of renin monoclonal antibody-based sandwich assays of renin
and prorenin, and use of renin inhibitor to enhance
prorenin immunoreactivity. Clin Chem. 1996;42:1051–1063.
28. Kagami S, Kuhara T, Okada K, Kuroda Y, Border WA, Noble NA. Dual effects of angiotensin II on the plasminogen/plasmin system in rat mesangial cells. Kidney Int. 1997;51:664–671.[Medline] [Order article via Infotrieve]
29.
van Kats JP, de Lannoy LM, Danser AHJ, van Meegen JR,
Verdouw PD, Schalekamp MADH. Angiotensin II type 1
(AT1) receptor-mediated accumulation of
angiotensin II in tissues and its intracellular half life
in vivo. Hypertension. 1997;30:42–49.
30.
Robertson AL, Khairallah PA. Angiotensin
II: rapid localization in nuclei of smooth and cardiac muscle.
Science. 1971;172:1138–1139.
31.
Eggena P, Zhu JH, Clegg K, Barrett JD. Nuclear
angiotensin receptors induce transcription of renin and
angiotensinogen mRNA. Hypertension. 1993;22:496–501.
32. de Mello WC. Is an intracellular renin-angiotensin system involved in the control of cell communication in heart? J Cardiovasc Pharmacol. 1994;23:640–646.[Medline] [Order article via Infotrieve]
33.
Haller H, Lindschau C, Erdmann B, Quass P, Luft FC.
Effects of intracellular angiotensin II in vascular smooth
muscle cells. Circ Res. 1996;79:765–772.
This article has been cited by other articles:
 |
|
 |
|
  M. Krop, R. van Veghel, I. M. Garrelds, R. J.A. de Bruin, J. M.G. van Gool, A. H. van den Meiracker, M. Thio, P. L.A. van Daele, and A.H. J. Danser Cardiac Renin Levels Are Not Influenced by the Amount of Resident Mast Cells Hypertension, August 1, 2009; 54(2): 315 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P. Singh, B. Le, R. Khode, K. M. Baker, and R. Kumar Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis Diabetes, December 1, 2008; 57(12): 3297 - 3306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M Dahms, L. J Olson, and J.-J. P Kim Strategies for carbohydrate recognition by the mannose 6-phosphate receptors Glycobiology, September 1, 2008; 18(9): 664 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Batenburg, R. J.A. de Bruin, J. M.G. van Gool, D. N. Muller, M. Bader, G. Nguyen, and A. H. J. Danser Aliskiren-Binding Increases the Half Life of Renin and Prorenin in Rat Aortic Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, June 1, 2008; 28(6): 1151 - 1157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J.V. McMurray, B. Pitt, R. Latini, A. P. Maggioni, S. D. Solomon, D. L. Keefe, J. Ford, A. Verma, J. Lewsey, and for the Aliskiren Observation of Heart Failure Tre Effects of the Oral Direct Renin Inhibitor Aliskiren in Patients With Symptomatic Heart Failure Circ Heart Fail, May 1, 2008; 1(1): 17 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Nguyen and A. H. J. Danser Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents Exp Physiol, May 1, 2008; 93(5): 557 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Feldt, U. Maschke, R. Dechend, F. C. Luft, and D. N. Muller The Putative (Pro)renin Receptor Blocker HRP Fails to Prevent (Pro)renin Signaling J. Am. Soc. Nephrol., April 1, 2008; 19(4): 743 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Feldt, W. W. Batenburg, I. Mazak, U. Maschke, M. Wellner, H. Kvakan, R. Dechend, A. Fiebeler, C. Burckle, A. Contrepas, et al. Prorenin and Renin-Induced Extracellular Signal-Regulated Kinase 1/2 Activation in Monocytes Is Not Blocked by Aliskiren or the Handle-Region Peptide Hypertension, March 1, 2008; 51(3): 682 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. N. Muller, B. Klanke, S. Feldt, N. Cordasic, A. Hartner, R. E. Schmieder, F. C. Luft, and K. F. Hilgers (Pro)Renin Receptor Peptide Inhibitor "Handle-Region" Peptide Does Not Affect Hypertensive Nephrosclerosis in Goldblatt Rats Hypertension, March 1, 2008; 51(3): 676 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Schweda, U. Friis, C. Wagner, O. Skott, and A. Kurtz Renin Release Physiology, October 1, 2007; 22(5): 310 - 319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Whaley-Connell, G. Govindarajan, J. Habibi, M. R. Hayden, S. A. Cooper, Y. Wei, L. Ma, M. Qazi, D. Link, P. R. Karuparthi, et al. Angiotensin II-mediated oxidative stress promotes myocardial tissue remodeling in the transgenic (mRen2) 27 Ren2 rat Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E355 - E363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Jan Danser, W. W. Batenburg, and J. H. M. van Esch Prorenin and the (pro)renin receptor--an update Nephrol. Dial. Transplant., May 1, 2007; 22(5): 1288 - 1292. [Full Text] [PDF]
|
|
|
|
|
|
A. Ichihara, Y. Kaneshiro, T. Takemitsu, M. Sakoda, T. Nakagawa, A. Nishiyama, H. Kawachi, F. Shimizu, and T. Inagami Contribution of Nonproteolytically Activated Prorenin in Glomeruli to Hypertensive Renal Damage J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2495 - 2503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Paul, A. Poyan Mehr, and R. Kreutz Physiology of local Renin-Angiotensin systems. Physiol Rev, July 1, 2006; 86(3): 747 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ichihara, Y. Kaneshiro, T. Takemitsu, M. Sakoda, F. Suzuki, T. Nakagawa, A. Nishiyama, T. Inagami, and M. Hayashi Nonproteolytic Activation of Prorenin Contributes to Development of Cardiac Fibrosis in Genetic Hypertension Hypertension, May 1, 2006; 47(5): 894 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.H. J. Danser and J. Deinum Renin, Prorenin and the Putative (Pro)renin Receptor Hypertension, November 1, 2005; 46(5): 1069 - 1076. [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Danser and J. Deinum Spotlight on Renin: Renin, Prorenin and the Putative (Pro)renin Receptor Journal of Renin-Angiotensin-Aldosterone System, September 1, 2005; 6(3): 163 - 165. [PDF]
|
|
|
|
 |
|
 F. C. Luft Cardiac Angiotensin Is Upregulated in the Hearts of Unstable Angina Patients Circ. Res., June 25, 2004; 94(12): 1530 - 1532. [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Carey and H. M. Siragy Newly Recognized Components of the Renin-Angiotensin System: Potential Roles in Cardiovascular and Renal Regulation Endocr. Rev., June 1, 2003; 24(3): 261 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Peters, R. Farrenkopf, S. Clausmeyer, J. Zimmer, S. Kantachuvesiri, M. G.F. Sharp, and J. J. Mullins Functional Significance of Prorenin Internalization in the Rat Heart Circ. Res., May 31, 2002; 90(10): 1135 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Hancock, D. J. Haskins, G. Sun, and N. M. Dahms Identification of Residues Essential for Carbohydrate Recognition by the Insulin-like Growth Factor II/Mannose 6-Phosphate Receptor J. Biol. Chem., March 22, 2002; 277(13): 11255 - 11264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Saris, M. M.E.D. van den Eijnden, J. M.J. Lamers, P. R. Saxena, M. A.D.H. Schalekamp, and A.H. J. Danser Prorenin-Induced Myocyte Proliferation: No Role for Intracellular Angiotensin II Hypertension, February 1, 2002; 39(2): 573 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Deinum, J. M.G. van Gool, M. J.M. Kofflard, F. J. ten Cate, and A.H. J. Danser Angiotensin II Type 2 Receptors and Cardiac Hypertrophy in Women With Hypertrophic Cardiomyopathy Hypertension, December 1, 2001; 38(6): 1278 - 1281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. E. D. van den Eijnden, J. J. Saris, R. J. A. de Bruin, E. de Wit, W. Sluiter, T. L. Reudelhuber, M. A. D. H. Schalekamp, F. H. M. Derkx, and A. H. J. Danser Prorenin Accumulation and Activation in Human Endothelial Cells : Importance of Mannose 6-Phosphate Receptors Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 911 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Saris, F. H. M. Derkx, R. J. A. De Bruin, D. H. W. Dekkers, J. M. J. Lamers, P. R. Saxena, M. A. D. H. Schalekamp, and A. H. Jan Danser High-affinity prorenin binding to cardiac man-6-P/IGF-II receptors precedes proteolytic activation to renin Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1706 - H1715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Saris, F. H. M. Derkx, J. M. J. Lamers, P. R. Saxena, M. A. D. H. Schalekamp, and A. H. J. Danser Cardiomyocytes Bind and Activate Native Human Prorenin : Role of Soluble Mannose 6-Phosphate Receptors Hypertension, February 1, 2001; 37(2): 710 - 715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Clausmeyer, A. Reinecke, R. Farrenkopf, T. Unger, and J. Peters Tissue-Specific Expression of a Rat Renin Transcript Lacking the Coding Sequence for the Prefragment and Its Stimulation by Myocardial Infarction Endocrinology, August 1, 2000; 141(8): 2963 - 2970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. C. De Mello and A. H. J. Danser Angiotensin II and the Heart : On the Intracrine Renin-Angiotensin System Hypertension, June 1, 2000; 35(6): 1183 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Almeida, V. Oliveira, J. R. Chagas, M. Meldal, M. A. Juliano, and L. Juliano Hydrolysis by Cathepsin B of Fluorescent Peptides Derived From Human Prorenin Hypertension, June 1, 2000; 35(6): 1278 - 1283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.H.J. Danser, J. J Saris, M. P Schuijt, and J. P van Kats Is there a local renin--angiotensin system in the heart? Cardiovasc Res, November 1, 1999; 44(2): 252 - 265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Dostal and K. M. Baker The Cardiac Renin-Angiotensin System : Conceptual, or a Regulator of Cardiac Function? Circ. Res., October 1, 1999; 85(7): 643 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A.M van Kesteren, J. J Saris, D. H.W Dekkers, J. M.J Lamers, P. R Saxena, M. A.D.H Schalekamp, and A.H.J. Danser Cultured neonatal rat cardiac myocytes and fibroblasts do not synthesize renin or angiotensinogen: evidence for stretch-induced cardiomyocyte hypertrophy independent of angiotensin II Cardiovasc Res, July 1, 1999; 43(1): 148 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. N. Muller, K. F. Hilgers, S. Mathews, V. Breu, W. Fischli, R. Uhlmann, and F. C. Luft Effects of Human Prorenin in Rats Transgenic for Human Angiotensinogen Hypertension, January 1, 1999; 33(1): 312 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. R. M. Osterop, M. J. M. Kofflard, L. A. Sandkuijl, F. J. t. Cate, R. Krams, M. A. D. H. Schalekamp, and A. H. J. Danser AT1 Receptor A/C1166 Polymorphism Contributes to Cardiac Hypertrophy in Subjects With Hypertrophic Cardiomyopathy Hypertension, November 1, 1998; 32(5): 825 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. de Lannoy, A.H. J. Danser, A. M.B. Bouhuizen, P. R. Saxena, and M. A.D.H. Schalekamp Localization and Production of Angiotensin II in the Isolated Perfused Rat Heart Hypertension, May 1, 1998; 31(5): 1111 - 1117. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||