(Hypertension. 1997;30:230-235.)
© 1997 American Heart Association, Inc.
Articles |
Downregulation of Renin Gene Expression by Interleukin-1
From the Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York (N.P., C.M.K., K.W.G.), and Cardiovascular Diseases Division, Departments of Internal Medicine and Physiology and Biophysics, University of Iowa College of Medicine, Iowa City (C.D.S.).
Correspondence to Kenneth W. Gross, PhD, Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263-0001. E-mail gross{at}acsu.buffalo.edu
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Abstract |
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Abstract The As4.1 cell line was established from a mouse kidney tumor by transgene-targeted tumorogenesis. These cells express high levels of renin mRNA from their endogenous renin gene and release approximately eightfold-more prorenin than active renin in culture. Levels of renin mRNA in As4.1 cells are decreased in a dose-dependent manner by the addition of physiological concentrations of cytokine interleukin-1 to the media. Stability of renin mRNA and initial rates of release of active renin and prorenin were not significantly altered by interleukin-1. In contrast, transcription initiated from a construct that consisted of 4.1 kilobases of renin 5' flanking sequence fused to a reporter gene (chloramphenicol acetyltransferase) was markedly inhibited by interleukin-1. On the basis of our findings, we conclude that downregulation of renin synthesis caused by interleukin-1 occurs primarily at the level of transcription and that DNA sequence or sequences mediating that effect are positioned within 4.1 kilobases upstream of the renin gene. The physiological relevance of this regulation is related to the events that occur during septic shock, characterized by hypotension, cardiovascular collapse, multiple organ failure, and high mortality. Unexpectedly, hypotension associated with septic shock does not lead to activation of the renin-angiotensin system. The hypotension in septicemia is believed to be mediated by the combined action of many modulators including cytokines, and data presented here suggest direct involvement of interleukin-1 in this process.
Key Words: renin • interleukin-1 • transcription • shock, septic • hypotension
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Septic shock syndrome, which results from severe infection or trauma, is characterized by severe hypotension that leads to cardiovascular collapse, multiple organ failure, and often death. Death from septic shock may be related to hypotension caused by a decrease in systemic vascular resistance and a large reduction in cardiac output. The hypotension in septicemia is believed to be mediated by the combined action of many modulators, including cytokines, prostaglandins, and complement components. An as-yet-unexplained feature of the hypotension associated with septic shock is that it does not lead to activation of the RAS. Cytokines, especially alpha and beta types of IL-1
and
IL-1ß, interleukin-6, and tumor necrosis factor, have been implicated
as primary mediators of the physiological response
to septicemia. Many in vivo findings point toward a pivotal role of
IL-1ß in septic shock–induced hypotension.1 A major
side effect observed in IL-1ß clinical trials is dose-limiting
hypotension.2 Also, specific blockade of IL-1ß at the
receptor level with an IL-1ß receptor antagonist (IL-1ra)
has been found to eliminate septic shock–induced hypotension in
rabbits.3 Moreover, mice with both chromosomal copies of
the IL-1ß–converting enzyme gene inactivated were
resistant to endotoxic shock.4 Here we present evidence that suggests that IL-1ß may have direct actions on the RAS, namely downregulation of renin gene expression. Since renin is a key participant in the regulation of systemic blood pressure and electrolyte balance through its fundamental role in the RAS, this downregulation could prevent the maintenance of blood pressure (ie, RAS response) and thus result in uncorrected hypotension.
To determine direct effects of IL-1ß on renin-expressing cells we used a clonal cell line, As4.1 (AmericanType Culture Collection [ATCC] No. CRL2193), of renal origin. This cell line was established from a kidney tumor of mice with a Ren-2 5' flank/Simian virus 40 (SV40) T-antigen transgene.5 Tissue-specific expression of the transgene was confirmed in transgenic animals.6 7 8 The As4.1 cell line maintains high expression of its endogenous renin gene in addition to the transgene over long-term culture and demonstrates several features that are characteristic of kidney juxtaglomerular cells, including the ability to store and release active renin.5 9 The endogenous renin gene expressed in the As4.1 cell line is Ren-1c. Thus, As4.1 cells may represent a unique model of juxtaglomerular cells with which to study in greater detail the mechanism of IL-1ß effects on renin expression during septicemia. In addition, the results from the present study will provide a basis for further studies of the effects of cytokines on renin synthesis in juxtaglomerular cells in vivo.
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Methods |
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Cell Culture
The renin-expressing As4.1 cell line (ATCC No. CRL2193) was cultured at 37°C in 10% CO2 atmosphere in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (GIBCO-BRL). At the beginning of the experiments cells were 90% confluent. Approximately 1 mL of media was used per 1x106 of cells in culture. Recombinant IL-1ß was purchased from R&D Systems and actinomycin D from Fisher.
Plasmid Constructions
Plasmid p-117CAT was constructed by inserting a renin promoter
fragment (+6 to -117, relative to the major transcription start site)
into the Xba I site adjacent to the CAT coding sequences of
plasmid pCAT-basic (Promega) as previously described.10
Plasmid R1C-4.1CAT was constructed by inserting the 5' flanking
sequences (-4100 to -118) of the BALB/c Ren-1c
gene isolated from a lambda clone, 
BALB-1, into a BamHI
site present at position -117 of the renin promoter in p-117CAT
plasmid.11 Plasmid DNA was prepared by the triton-lysis
method12 and two sequential cesium chloride/ethidium
bromide equilibrium centrifugation steps.
DNA Transfections
As4.1 cells were transfected by electroporation13
using a Cell Porator and electroporation chambers with 0.4 cm electrode
spacing (Gibco-BRL). Conditions for electroporation were as follows:
1x107 cells were resuspended in 1 mL of 1x HeBS (25
mmol/L HEPES, pH 7.05, 140 mmol/L NaCl, 5
mmol/L KCl, 0.75 mmol/L
Na2HPO4, 6 mmol/L glucose) with DNA
concentration of 25 to 50 µg/mL, plus 250 µg/mL of
sonicated salmon sperm DNA, added as carrier. The cells were then
exposed to a single electric impulse of 300 V at a capacitance setting
of 1180 µF.
To correct CAT values in each experiment for transfection efficiency, cells were cotransfected with 5 µg of plasmid containing RSV promoter driving ß-galactosidase (RSV–ß-gal). Transfection of promoterless CAT plasmid, pCAT-basic (Promega) into As4.1 cells, used to determine the background in these assays, did not result in any significant CAT activity (data not shown).
Enzyme Assays
Chloramphenicol Acetyltransferase
Cells were harvested 48 to 72 hours post-transfection and
resuspended in 0.25 mol/L Tris, pH 8.0. The extract was
subjected to three freeze-thaw cycles, and prior to CAT assays extracts
were heated to 60°C for 10 minutes. The protein concentration was
determined by the method of Bradford14 using bovine serum
albumin as standard. CAT activity was determined as described
by Gorman et al15 except that n-butyryl CoA was
substituted for acetyl-CoA in the assay. Equal amounts of protein (35
µg) were assayed for CAT activity in 0.25 mol/L Tris, pH 8.0,
0.125 µCi of [14C]-chloramphenicol (55 mCi/mmol, 1
Ci=37 GBq) obtained from Amersham. Amount of butyrylated
[14C]-chloramphenicol generated in the reaction was
determined by thin-layer chromatography. CAT activities
were given as percent conversion of chloramphenicol obtained in the
enzyme assay with 35 µg of cellular protein. Values in each
experiment were corrected for transfection efficiency by measuring
ß-galactosidase activity in the same lysates. All radioactive signals
were quantified by phosphorimagery using Imagequant software
(Molecular Dynamics).
ß-Galactosidase
ß-Galactosidase activity was determined using Galacto-Light
Plus chemiluminescence reporter assay (Tropix) according to the
manufacturer's instructions. Chemiluminescence was measured on a
Monolight 2010 Luminometer (Analytical Luminescence Laboratory).
Results were expressed as relative light units per microgram of
cell lysate.
Renin
To determine the amount of total renin activity, prorenin was
activated (converted to active renin) with trypsin treatment
(0.3 mg/mL, 1 hour at room temperature) as previously
described.16 Samples used to measure only active renin
were not treated with trypsin. Prorenin content was estimated by
subtraction of active renin activity from total renin activity. After
inhibition of trypsin with phenylmethylsulfonyl fluoride
(1 mmol/L), renin assays were performed with
Angiotensin-I[125I] Radioimmunoassay Kit (Du
Pont) according to the manufacturer's instructions. Activity
measurements were made by incubation of samples with bilateral
nephrectomized rat plasma as a source of renin substrate
angiotensinogen. The amount of released Ang I was
determined by the same kit. Renin activity is defined as nanograms of
Ang I formed by 1 mL of culture media for 1 hour. The entire experiment
was performed within 1 day without freezing the samples. The media also
were assayed for renin activity in the presence of specific renin
inhibitor (CP-71,362, a gift from Pfizer Inc, New York, NY)
(data not shown). The specific renin inhibitor caused full
inhibition of both active and total renin activities. To test for
nonspecific degradation of the substrate, an assay was performed with
the culture media from Ltk- (mouse fibroblast) control
cell line. No significant renin activity was detected in this assay
(data not shown).
Northern Blot Analysis
Total RNA was isolated from As4.1 cells using the method based
on the widely used guanidinium thiocyanate/acid
phenol/chloroform procedure in which Ultraspec RNA isolation kit
(Biotecx) is used, according to the manufacturer's instructions. Total
RNA samples (30 µg) were analyzed for renin mRNA levels by
Northern blot analysis17 with mouse submandibular
Ren-2d cDNA probe18 and human GAPDH
probe (Clontech). Probes were labeled with dCTP[P32]
(Amersham) by random-priming (kit from Promega). After quantification
of renin probe signals by phosphorimagery, blots were stripped of the
renin probe and rehybridized with GAPDH probe for determination of
GAPDH mRNA levels.
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Results |
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The As4.1 cell continuously expresses high levels of renin mRNA when grown in standard culture media. The addition of IL-1ß caused a dose-dependent decrease in renin mRNA levels (Fig 1A
). IL-1ß affected renin mRNA levels
in As4.1 cells at a concentration (ED50 is 30 pg/mL)
(Fig 1B) that correlates well with IL-1ß levels found in normal human
serum and in serum of septic shock patients (2.5±2 and 120±17
pg/mL, respectively).19 IL-1ß (1 ng/mL)
caused rapid decreases in renin mRNA, approximately 7-fold, within 24
hours (Fig 2). Further increases in
IL-1ß concentration (Fig 1B) or incubation time (Fig 2) did not
result in a further decline in renin mRNA. The observed effect may be
specific to IL-1ß, since another cytokine elevated during
sepsis, namely IL-6, did not significantly affect renin mRNA levels
(data not shown). Tumor necrosis factor- was found to be extremely
toxic to the As4.1 cells in the concentrations usually used in cell
culture studies (data not shown).
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The kinetics of renin mRNA decay do not seem to be affected
significantly by IL-1ß after transcription is blocked with
actinomycin D (Fig 3). In control
experiments, actinomycin D added to As4.1 cells in culture inhibited
incorporation of [5,6-3H]-uridine into total RNA by more
than 95% within 1 hour (data not shown).
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) and controls (
);
renin mRNA levels from IL-1ß–treated cells (
) and controls
(
).
As4.1 cells grown in culture media released both active renin and
prorenin linearly with time during the 72 hours of the experiment (Fig 4). The amount of prorenin released by
As4.1 cells was approximately 8-fold higher (8 ng of Ang I formed/mL of
media/h) than active renin (approximately 1 ng of Ang I formed/mL of
media/h) after 72 hours in cell culture (Fig 4). Release of active
renin and prorenin from As4.1 cells in response to IL-1ß was not
significantly affected at 1 or 2 hours (data not shown) up through 24
hours (Fig 4). After 24 hours of IL-1ß incubation, a decrease in the
amounts of both prorenin and active renin was observed.
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The As4.1 cells contain a transgene incorporated into their chromosomal
DNA. The transgene consists of SV40 Large T antigen gene (an
oncogene) under the regulation of 4.6 kb of 5' upstream region of the
Ren-2 gene. If IL-1ß affects transcription of the renin
gene, and if the responsive DNA regulatory regions mediating this
effect are positioned within the 4.6-kb fragment, then the
effects on expression of the transgene and endogenous
Ren-1c gene in As4.1 cells would be expected to
be similar. Indeed, Northern blot analysis revealed that the
steady state levels of endogenous renin mRNA and T-antigen
mRNA expressed from the transgene (Fig 5)
were similarly decreased by IL-1ß. In contrast, the levels of control
GAPDH mRNA were unaltered by IL-1ß (Fig 5).
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To independently verify the effects of IL-1ß on the renin gene
transcription, the As4.1 cells were transfected with DNA plasmids
containing the Ren-1c 5' flanking region (from
+6 to -4100 base pairs from the transcription start site) controlling
transcription of the CAT reporter gene. Rapid growth of As4.1 cells is
believed to be mediated by the high levels of SV40 Large T
antigen expressed from the transgene. Since IL-1ß suppressed
T-antigen expression, this downregulation could in turn affect the
general rate of transcription in these cells. In an effort to control
for this, an RSV promoter driving CAT reporter gene
(RSV-CAT) was used to determine nonspecific effects of
IL-1ß on transcription in As4.1 cells. The results shown in Fig 6 demonstrate that RSV-CAT activity in
control cells (87.8±6.0% chloramphenicol converted by 35 µg of cell
extracts) was approximately 3-fold higher than in IL-1ß–treated
cells (29.8±3.5%). On the other hand, IL-1ß caused a much more
significant decrease in transcription from the -4.1
Ren-1c–CAT reporter gene construct,
approximately 22-fold (39±5.2% in control versus 1.8±0.5% after
IL-1ß treatment) (Fig 6). Since nonspecific effects of IL-1ß on
transcription as measured with RSV-CAT were 3-fold, and the total
effect observed with -4.1
Ren-1c–CAT was 22-fold, it can be
calculated that specific inhibition of -4.1
Ren-1c–CAT transcription in response
to IL-1ß is approximately 7-fold. An effect of this magnitude is
consistent with the decrease observed in the Northern blot
experiments (Fig 1
).
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Promoterless plasmid, pCAT-basic, used to determine the background of CAT activity in these assays, did not show any significant CAT activity (data not shown). The transcription initiation site used by transfected Ren-1c–CAT constructs is the same one found for endogenous Ren-1– and Ren-2–gene–derived renal transcripts.10
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Discussion |
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In the present report, we show that cytokine IL-1ß inhibits, at physiological concentrations, transcription of the renin gene, in cultured, renal-derived, renin-expressing As4.1 cells. Our data indicate not only that the IL-1ß effect occurs primarily at the level of transcription but also that DNA regulatory region or regions mediating this effect are present on 4.1 kb of the renin gene 5' regulatory region. The inhibitory effect of the IL-1ß on renin expression does not appear to be caused by general inhibition of transcription and proliferation of As4.1 cells.
Our findings are consistent with previously described effects of IL-1ß on renin mRNA in primary human decidual cells that express renin.20
The dynamics of renin mRNA decay do not seem to be affected
significantly by IL-1ß after the addition of actinomycin D (Fig 3).
The possibility remains that unknown regulatory proteins, the
expression of which is blocked by inhibition of transcription,
may affect renin mRNA stability under IL-1ß. These putative proteins
would have to exert their effects by binding to a
six-nucleotide stretch on renin mRNA (from +1 to +6), since
only that sequence is shared between endogenous renin mRNA
and mRNA transcribed from CAT and T-antigen reporters, which were
affected by IL-1ß similarly. Whether such an effect underlies the
discrepancy in apparent half-life of renin mRNA as estimated from
IL-1ß treatment alone (Fig 2) compared with that obtained by
actinomycin D treatment (Fig 3) remains to be elucidated. In any event,
the magnitude of the transcriptional effects observed (Figs 5 and 6)
can adequately account for the steady state levels of mRNA found.
Since inhibition of renin release by IL-1ß did not occur until the second day of exposure, the effects on renin release appear to be secondary to the decrease in renin synthesis. Alternatively, if intracellular levels of renin are not altered over the time of experiment, observed changes in the extracellular renin concentration may represent a slow effect on renin release. In this regard, pulse-chase radiolabeling experiments in which 35S-methionine was used9 indicate that turnover of intracellular prorenin is complete within 5 hours. In contrast, turnover of intracellular active renin is much slower (about 72 hours), although precise determination is obscured by the fact that cells continuously grow throughout the experiment. Therefore, while the effect of IL-1ß on extracellular prorenin most probably reflects an inhibition of renin synthesis, given the time frame of the experiment, extracellular active renin levels may be influenced by a combination of inhibition of synthesis and slow effects on release. Although the effects of IL-1ß on renin accumulation were not directly measured, the observed decrease in transcription of the renin gene in response to IL-1ß may completely account for the changes in steady state renin mRNA levels after IL-1ß treatment. Thus, while effects of IL-1ß on processes other than transcription are possible, they seem less likely to exist or are less pronounced.
IL-1ß is synthesized during inflammation and sepsis.1 Sepsis and septic shock are heterogeneous clinical syndromes that are usually triggered by severe microbial infection. Septic shock is defined as severe sepsis accompanied by hypotension.21 Many of the effects of IL-1ß are beneficial at the onset of infection, but when produced for extended periods of time or in excessive quantities, this cytokine has been directly linked to the development of hypotension, shock, multiple organ failure, and death.1
IL-1ß produced in septicemia causes an increase in the expression of iNOS in peripheral vasculature, which causes a decrease in vascular resistance through relaxation of vascular smooth muscle. NO produced by iNOS has been hypothesized to be responsible for hypotension in septic shock. Inhibition of NOS activity during sepsis has produced conflicting results (see Reference 2121 for review, also References 22 and 2322 23 ) presumably because NO produced by iNOS has also been shown to be beneficial through its antimicrobial activity. Moreover, these studies are further complicated by the fact that most of them have used nonselective NOS inhibitors. Blanket inhibition of all NOS isozymes (inducible and continuously expressed) may have resulted in the side effects observed in these studies.
The diversity of the molecular origins, targets, and actions of NO makes it difficult to anticipate the consequences of inhibiting its production in disease. In some models of sepsis, plasma NO concentration did not correlate with outcome of the septic shock.24 In genetic studies, mice with both chromosomal genes for iNOS inactivated did not show differences in survival rate after induced septic shock compared with the controls.25 Interestingly, other reports on the iNOS knockouts indicated differences in hypotension onset in anesthetized animals.26 This use of different animal systems, as well as the specific states and causes that result in septic shock in patients, may have complicated establishment of a single cause for the hypotension during septicemia, reflecting the fact that blood pressure homeostasis entails interactions among compensatory constellation of factors.
IL-1ß produced during septicemia may also have a direct action on the RAS, which is, according to our findings, to decrease synthesis of renin. Such an effect would prevent activation of the RAS, diminish its contribution to the maintenance of blood pressure, and ultimately contribute to the observed hypotension. Indeed, in some patients27 infusion of Ang II caused a reversal of septic shock symptoms. Therefore, at least in some cases of septic shock, impairment of RAS function could be responsible for the development of hypotension.
The use of homogeneous cells in culture allowed us to test for direct effects of cytokines on renin-producing cells. These findings should help us work toward determination of the exact mechanism or mechanisms of cytokine regulation of renin synthesis in As4.1 cells, and should give direction to further in vivo studies aimed at understanding renin gene regulation in the important area of septic shock–induced hypotension.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants HL35792, HL48459, and CA16056 and the Roswell Park Alliance Foundation. C.D. Sigmund is an Established Investigator of the American Heart Association.
Received July 5, 1996; first decision August 7, 1996; accepted January 16, 1997.
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M. J. Ryan, T. A. Black, K. W. Gross, and G. Hajduczok Cyclic mechanical distension regulates renin gene transcription in As4.1 cells Am J Physiol Endocrinol Metab, October 1, 2000; 279(4): E830 - E837. [Abstract] [Full Text] [PDF]
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R. F. Husted, C. Zhang, and J. B. Stokes Concerted actions of IL-1beta inhibit Na+ absorption and stimulate anion secretion by IMCD cells Am J Physiol Renal Physiol, December 1, 1998; 275(6): F946 - F954. [Abstract] [Full Text] [PDF]
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