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inhibits renin gene expression
Institut für Physiologie I, Universität Regensburg, D-93040 Regensburg, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Renin, produced
in renal juxtaglomerular (JG) cells, is a fundamental regulator of
blood pressure. Accumulating evidence suggests that cytokines may
directly influence renin production in the JG cells. TNF-
, which is
one of the key mediators in immunity and inflammation, is known to
participate in the control of vascular proliferation and contraction
and hence in the pathogenesis of cardiovascular diseases. Thus TNF-
may exert its effects on the cardiovascular system through modulation
of renal renin synthesis. Therefore we have tested the effect of
TNF- on renin transcription in As4.1 cells, which represent
transformed mouse JG cells, and in native mouse JG cells in culture.
Renin gene expression was also determined in mice lacking the gene for
TNF- (TNF- knockout mice). TNF- inhibited renin gene
expression via an inhibition of the transcriptional activity, targeting
the proximal 4.1 kb of the renin promoter in As4.1 cells. TNF- also
attenuated forskolin-stimulated renin gene expression in primary
cultures of mouse JG cells. Mice lacking the TNF- gene had almost
threefold higher basal renal renin mRNA abundance relative to the
control strain. The general physiological regulation of renin
expression by salt was not disturbed in TNF- knockout mice. Our data
suggest that TNF- inhibits renin gene transcription at the cellular
level and thus may act as a modulator of renin synthesis in
(physio)pathological situations.
As4.1 cells; juxtaglomerular cells; knockout mice
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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REGULATION of arterial blood pressure is one of the fundamental processes of homeostasis. Blood pressure in mammals is under tight control of various neural and humoral factors, which act in concert to ensure optimal values for the function of the organism according to the environmental changes. The plasma renin-angiotensin-aldosterone-system (RAAS) is among the principal humoral regulators of arterial blood pressure. Although ANG II is the main effector of the system, renin is the key factor that determines the amount of generated ANG II and hence the activity of the RAAS in most mammalian species, including humans. Renin found in circulation is exclusively produced in the juxtaglomerular (JG) cells of the kidneys (10, 32). Renin production in the JG cells is precisely regulated at different checkpoints, starting with the transcription of renin gene, going through the cleavage of the precursor renin molecule, and ending with the processing and storage of renin in secretory granules. The rate of renin gene expression is the first limiting step in the synthesis of renin. Therefore renin gene expression is under the strict control of various factors, including sodium load, blood pressure, sympathetic renal nerve activity, macula densa signal, as well as catecholamines, ANG II, prostaglandins, nitric oxide, and endothelins (36, 37). All these factors interact to determine the actual renin production under both physiological and pathophysiological conditions (29).
During the past decade increasing evidence has been accumulated
that inflammatory cytokines also are involved in the regulation of
renal renin transcription. Thus it was found that IL-1 and oncostatin M
inhibit renin gene expression in the JG-like cell line As4.1 (3,
11, 25). Transient transfections in the mouse adrenocortical
tumor cell line Y-1 have shown that human renin promoter is responsive
to TNF- (5). On the other hand, inflammatory cytokines
and particularly TNF-, which is an archetypal representative of the
cytokine family, seem also to be engaged in blood pressure homeostasis
(7, 15). Thus TNF- was found to be involved in the
control of vascular contraction and proliferation (4, 26).
Although blood mononuclear cells represent the main source of TNF-,
it is also reported to be produced in other cell types, including
mesangial and proximal tubule cells of kidneys (2, 38).
Remarkably, TNF- is also produced in the medullar thick ascending
limb of Henle's loop (mTALH) under baseline conditions (20). Therefore it would not be unlikely if TNF- could
play an important role in the regulation of renal functions and in the
control of renin production in JG cells in particular. To test the
hypothesis that TNF- may be a relevant regulator of renin
transcription, we have studied renin gene expression in primary
cultures of mouse JG cells and in As4.1 cell line. The As4.1 cells were
isolated from mouse kidney after SV40/T-antigen transformation
(28). They are believed to derive from JG cells, because
they carry the most characteristic feature of native JG cells, namely
to produce renin in a regulated manner. As4.1 cells are a
well-established model for studying renin transcription (3, 11,
25, 34). We have also studied the effect of genetic knockout of
TNF- on renin gene expression in vivo.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The experiments were performed according to the "Guiding Principles for Research Involving Animals and Human Beings" of the American Physiology Society (1).
Cell Cultures
As4.1 cells were obtained from the American Type Culture collection (ATCC-CRL-2193). The cells were cultured in Dulbecco's modified essential media (Biochrom KG) supplemented with 10% fetal calf serum, L-glutamine and Na-pyruvate, 100 U/ml penicillin, and 100 µg/ml streptomycin and incubated at 37°C in a humidified atmosphere containing 10% CO2. At the beginning of the experiments cells were confluent.Primary cultures of JG cells were established from C57Bl/6 mice. For a cell preparation, two male mice (4-6 wk old) were killed by cervical dislocation. The kidneys were extirpated, decapsulated, and minced with a razorblade at 4°C. The minced tissue was incubated under gentle stirring for 90 min at 37°C in 50 ml buffer I [(in mmol/l): 130 NaCl, 5 KCl, 2 CaCl2, 10 glucose, 20 sucrose, and 10 Tris, pH 7.4] supplemented with 0.25% trypsin (Sigma) and 0.05% collagenase A (Boehringer). Next the tissue was sieved through a 22.4-µm screen. The sieved cells were collected, washed, and resuspended in 4 ml of buffer I. The cell suspension was divided into two tubes each containing 30 ml 30% isosmotic Percoll (Pharmacia) in buffer I. After 30 min of centrifugation at 4°C and 25,000 g, four cellular layers with different specific renin activity were obtained. The cellular layer (density = 1.07 g/ml) with the highest specific renin activity was used for cell culture. These cells were resuspended in 4 ml Dulbecco's modified essential media (Biochrom KG) supplemented with 2% fetal calf serum, L-glutamine and Na-pyruvate, 100 U/ml penicillin, and 100 µg/ml streptomycin. The cells were aliquoted at 0.5 ml into a 24-well plate and were incubated at 37°C in a humidified atmosphere supplemented with 5% CO2. Experiments were started 24 h after plating.
Animal Experiments
Male TNF- 
/ mice and their control wild-type strain
B6129SF2/J, 4-6 wk old, were purchased from Jackson Laboratory.
Three groups of mice each composed of 16 animals (8 wild-type and 8 TNF- / mice), were used for experiments. Animals in group
1 received no treatment and served as controls. Animals in
group 2 were kept on low-salt diet (0.02% wt/wt) for 10 days. During the last 3 days of the period, the mice from this group
received additionally the angiotensin-converting enzyme (ACE) inhibitor ramipril (10 mg · kg
1 · day1)
via the drinking water. Animals in group 3 were fed with
high-salt diet (8% wt/wt) for 10 days. At the end of the experiments
animals were killed by cervical dislocation and the kidneys were
extirpated, decapsulated, and snap-frozen at 80°C until total RNA
was isolated.
RNA Isolation
Total RNA was isolated from As4.1 cells and kidneys according to the method of Chomczynski and Sacchi (6).Total RNA from cultured JG cells was isolated from each well separately in 30-µl end volume using Qiagen RNeasy Spin Columns.
RT-PCR
RT-PCR was performed using standard protocols as described (12). Five microliters total RNA extract from primary JG cultures or 1 µg total RNA from As4.1 cells was reverse transcribed in a total volume of 20 µl. The primers used for amplification of specific mouse renin and
-actin cDNA fragments were already
described (12). A 289-bp TNF-receptor type I (TNF-RI) cDNA
fragment was amplified using forward primer 5'-CGG GAT CCT CTC ACA GGA
ATA CTA TG-3' and reverse primer 5'-GGA ATT CTG TCG ACA GCT GCC AGA AT-3'. A 218-bp TNF-receptor type II (TNF-RII) cDNA fragment was amplified using forward primer 5'-CGG GAT CCT CAC TGG ACT AGT CCC TT-3'
and reverse primer 5'-GGA ATT CAC ACT GCC TGA GGT AAT T-3'. Two (for
-actin, TNF-RI, and TNF-RII fragments) or three (for renin fragment)
microliters cDNA were amplified in a total volume of 20 µl.
Thirty-five cycles were used for the reactions with specific primers
for renin, TNF-RI, and TNF-RII cDNAs, while for the reactions with
specific primers for the -actin sequence, 28 cycles were used. PCR
products were separated on a 2% agarose and viewed with ethidium bromide.
RNase Protection Assay
RNase protection assays for mouse renin and-actin (used as
an internal control) were performed as described previously (11, 34).
Transient Transfection
The mouse renin promoter/luciferase constructs were produced by amplifying the 5'-flanking sequence of the mouse renin gene from a commercially available mouse genomic DNA (Clontech) using the expanded long template PCR system (Boehringer Mannheim). Using the primers 5'-GCGTGCATGTGGTGTACATAG-3' and 5'-GAGACTGAAGGTGCAAGG-3', a 4.1-kb fragment (4071 to +98) of the mouse renin promoter (GenBank accession
no. L78789) was generated and inserted in the polylinker site of vector
pGL3 Enhancer (Promega), which contains a modified coding region of the
firefly luciferase. As4.1 cells were split 24 h before
transfection in 24-well culture plates with a density of 1 × 105 cells/well. Transfection was performed using 6 µl
Fugene 6 transfection reagent (Roche). For each transfection, 1 µg of
DNA construct was transfected. To correct luciferase activity to the
transfection efficiency, As4.1 cells were cotransfected with 0.01 µg
of a plasmid containing an SV40 promoter driving Renilla
luciferase (pRL-SV40 Renilla, Promega). The medium was
replaced 12 h after transfection, and the cells were incubated
with the test substances.
Luciferase activity was measured with the Dual Luciferase Assay Kit from Promega, according to the manufacturer's instructions. Light production was measured 20 s first for firefly and then for Renilla luciferase activity in a Lumat LB 9507 luminometer (Berthold). The relative luciferase activity was calculated as firefly luciferase-to-Renilla luciferase ratio.
Renin Radioimmunoassay
Active renin was measured using the ANG I radioimmunoassay kit of Sorin Biomedica.As4.1 cells.
As4.1 cells were split in 24-well culture plates with a density of
1 × 105 cells/well. Cells were incubated overnight
with 10 ng/ml TNF-, and then medium was changed and cells were
treated with 1 ng/ml TNF- for 20 h. Control cells were
incubated just with standard medium. (Pro)renin activity in
supernatants was measured after trypsin activation of prorenin to renin
as described (21).
JG cells. Experiments on renin secretion in primary cultures of mouse JG cells were performed throughout 20 h of incubation. Supernatants were then collected and spun at 10,000 g to remove cellular debris. Five-microliter aliquots were taken for the determination of the amount of secreted active renin.
Mice.
Wild-type (B6129SF2/J) and TNF- / mice were killed by
decapitation to minimize stress-induced variations of the plasma renin
content, which could be up to 100-fold. Blood was collected and plasma
was obtained according to Ref. 19, and plasma
renin activity (PRA) was determined.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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As4.1 Cells and Native JG Cells Express Specific Receptors for
TNF-
exerts its effects through interacting with two specific
receptors on the cellular surface, namely TNF-RI and TNF-RII (17,
18, 30). Using RT-PCR, we checked whether As4.1 cells and JG
cells express mRNA for these receptors. TNF-RI and TNF-RII were found
in As4.1 and JG cells. Moreover, the expression pattern of the TNF
receptors was identical in both cell types, namely the expression of
TNF-RII was higher than the expression of TNF-RI (Fig.
1).
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TNF- Inhibits Renin Gene Expression and Renin Promoter Activity
in As4.1 Cells
on As4.1 cells, we studied the effect of TNF- on renin gene
expression. TNF- suppressed renin mRNA formation at all concentrations tested, with a maximal inhibition at 100 ng/ml (4-fold)
(Fig. 2A). Time chase
experiments on the effect of TNF- on renin gene expression revealed
that TNF- significantly decreased renin mRNA abundance after 8-h
incubation. The maximum inhibition was observed between the 16th and
the 20th hour of incubation (Fig. 2B). To check whether
changes in the transcription rate of renin gene was responsible for the
changes in the renin mRNA levels during incubation with TNF-, we
performed transient transfections with a 4.1-kb proximal promoter
fragment of the mouse renin gene in As4.1 cells. Renin promoter
activity was also effectively suppressed by TNF-. This suppression
was ~30% after 16 h and almost threefold after 20 h of
treatment with TNF- (Fig. 3), implying
that changes in the transcription of the gene rather than
posttranscriptional modifications are mainly responsible for the effect
of TNF- on renin mRNA synthesis.
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TNF- Inhibits Renin Gene Expression in Primary Cultures of JG
Cells
on renin
transcription in As4.1 cells may have been due to their neoplastic transformation, we have also performed studies on primary cultures of
native JG cells. As the basal expression of renin in cultured JG cells
is at the lowest limit of sensitivity of the presently known methods of
measurement, we studied the effect of TNF- on forskolin-stimulated
renin gene expression. Under such experimental conditions, TNF- lead
to a decrease in renin mRNA abundance also in native JG cells as shown
by RT-PCR (Fig. 4A).
Densitometric measurements of amplified renin cDNA bands showed that
forskolin stimulated renin gene expression ~3-fold and TNF-
attenuated the forskolin-stimulated renin transcription by >30% (Fig.
4B).
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Effect of Genetic Knockout of TNF- on Renin Gene Expression In
Vivo
could inhibit renin
transcription in vivo, too (Fig. 5).
Because the known pharmacological inhibitors of TNF- production
belong to the group of phosphodiesterase blockers, which modify the
synthesis of renin per se, and because prolonged treatments of mice
with TNF- or with neutralizing antibodies against TNF- cannot yet
be conducted, we characterized renin gene expression in mice lacking
TNF- (TNF- / mice). These genetically knockout mice turned
out to have almost threefold higher basal expression of renin mRNA
compared with their corresponding wild-type strain. When stimulated
with low-salt diet plus ACE inhibitor (ramipril), renin gene expression
increased with a factor of 10 in both wild-type and TNF- knockout
mice. Renin gene transcription was twofold inhibited both in wild-type
mice and in TNF- / mice by a high-salt diet. Thus TNF- may be
a negative modulator of renin expression in vivo, without being
involved in the physiological control of renin expression by salt
intake.
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Renin Release and TNF-
As4.1 cells.
As4.1 cells are known to secrete renin constitutively, rather than
through a regulated pathway (16). As >90% of the renin secreted is in the form of inactive prorenin (14), we have
converted prorenin to active renin by trypsin incubation. Due to the
slow decline of renin mRNA in response to TNF-, we have pretreated As4.1 cells with TNF- overnight. Then the medium was changed and the
cells were treated with TNF- for another 20 h, during which
prorenin secretion was determined. We found that TNF- suppressed the
synthesis of (pro)renin in As4.1 cells down to 10% of the basal level
(Fig. 6A).
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JG cells in vitro and in vivo.
In primary cultures of mouse JG cells, renin secretion reflects
the regulated exocytosis of stored active renin, rather than the de
novo synthesis rate of (pro)renin, which is very low in the cultured
native JG cells. As shown in Fig. 6B, TNF- did not significantly change renin release from primary cultures of mouse JG
cells. Finally, we also determined PRA as an indirect measure for renin
secretion in TNF- / mice and their wild-type controls. The PRA
values in both strains displayed a rather broad scatter, which did not
allow us to detect a possible minor difference between the two strains
(Fig. 6C).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TNF- is a cytokine known predominantly for its role in immune
responses (35). However, TNF- seems also to have
important functions for the cardiovascular system. Changes in blood
pressure could change TNF- production, and conversely TNF- could
induce changes in arterial blood pressure. TNF- mRNA and protein are markedly increased after hypertensive stress, and also TNF-
secretion from blood monocytes is increased in patients with essential
hypertension (7, 15). On the other hand, TNF- is a
well-established stimulator of the expression of inducible nitric oxide
synthase (iNOS) in vascular smooth muscle cells (VSMCs), and hence of
NO production, leading to a vasodilatation and fall in blood pressure
(24, 33). The synthesis of ceramide, which is one of the
second messengers in TNF- signaling, was impaired in VSMCs of
spontaneously hypertensive rats (13). TNF- is also a
relevant depressant of cardiac function (22). However,
much less is known about the action of TNF- on the systematic
regulators of blood pressure. Therefore, we have studied the effect of
TNF- on renal renin gene expression. Renin, produced in the JG cells
of the kidneys, is the limiting factor that sets the activity of the
RAAS system, which in turn plays a pivotal role in the regulation of
blood pressure. We found that TNF- inhibits renin transcription via
suppression of renin promoter activity in the transformed JG-cell line
As4.1. Downregulation of renin gene expression by inflammatory
cytokines (IL-1, oncostatin M) in the juxtaglomerular cell line As4.1
was already reported by others and ourselves (11, 25).
However, it was also found in this context that IL-1 had no effect on
renin gene expression in native JG cells in culture (11),
consistent with the fact that there were no IL-1-specific receptors
identified on JG cells (31). These findings raised the
possibility that the downregulation of renin transcription by
inflammatory cytokines in As4.1 cells may be an "artefact" of their
transfection with the SV40/T-antigen and the subsequent immortalization.
In the present study we show that TNF- inhibits renin gene
expression not only in As4.1 cells but also in cultured native JG cells
and that both As4.1 cells and native JG cells express TNF-RI and
TNF-RII, which are the specific receptors for TNF-. These results
suggest that TNF- can in principle directly affect renal renin
production via inhibition of renin gene transcription, indicating a
novel pathway in the cellular control of renin gene expression.
Our observation that renal renin mRNA levels were substantially
increased in TNF- / mice would fit with the concept of an
inhibitory effect of TNF- on renin gene expression also in vivo. We
are aware, however, that the data obtained with TNF- / mice
cannot prove a regulatory function of TNF- for renin synthesis. The
physiological impact of TNF- in the control of renin synthesis and
the situations in which it becomes active remain therefore to be
clarified in future studies.
The findings that TNF- inhibited prorenin synthesis in As 4.1 cells,
but did not affect regulated exocytosis of active renin from native JG
cells, suggest that TNF- acts predominantly on the slow regulation
of (pro)renin synthesis rather than on the rapid regulation of
exocytosis of active renin. The quite normal PRAs found in
TNF- / mice would fit with this conclusion. It should be
mentioned in this context, however, that PRA in mice is considered not
as an ideal indicator of renal renin secretion in vivo as in other species.
The possible interactions between TNF- and the RAAS are not
restricted just to renin. TNF- was reported to inhibit ACE activity and expression in endothelial cells (23, 27). TNF-
production is significantly increased by ANG II in mTALH in vitro and
also in mTALHs of ANG II-dependent hypertensive rats (8,
9). Thus downregulation of renin gene transcription by TNF-
could be an important mechanism in the compensatory activities of the organism against elevated blood pressure, and also it could contribute to a negative-feedback loop in the RAAS.
In summary, in this study we provide evidence that TNF- is a potent
and specific downregulator of renin gene expression in normal and
immortalized JG cells in vitro, acting through inhibition of the renin
promoter. Because TNF- is a mediator, which is produced principally
under pathological conditions, the significance of the novel TNF-
effect on renin gene expression during physiological but also under
pathophysiological conditions in vivo remains to be elucidated in
further experiments.
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ACKNOWLEDGEMENTS |
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This study was financially supported by Deutsche Forschungsgemeinschaft Grant KU-859/2-4.
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FOOTNOTES |
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Address for reprint requests and other correspondence: V. Todorov, Institut für Physiologie I, Universität Regensburg, D-93040 Regensburg, Germany (E-mail: vladimir.todorov{at}vkl.uni-regensburg.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
June 27, 2002;10.1152/ajpregu.00142.2002
Received 1 March 2002; accepted in final form 25 June 2002.
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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