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(Hypertension. 2007;50:939.)
© 2007 American Heart Association, Inc.

Original Articles

Peroxisome Proliferator-Activated Receptor- Is Involved in the Control of Renin Gene Expression

Vladimir T. Todorov; Michael Desch; Nina Schmitt-Nilson; Anelia Todorova; Armin Kurtz

From the Institute of Physiology, University of Regensburg, Regensburg, Germany.

Correspondence to Vladimir T. Todorov, Institute of Physiology, University of Regensburg, D-93040 Regensburg, Germany. E-mail vladimir.todorov{at}vkl.uni-regensburg.de

	Abstract

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Based on the presence of a functional retinoic acid receptor/retinoid X receptor transcription factor binding sequence (hormone-responsive element) in the renin gene enhancer and on the fact that the peroxisome proliferator-activated receptors (PPARs) bind to DNA as heterodimers with retinoid X receptors, we speculated that PPARs are involved in the regulation of renin gene expression. To test this hypothesis, we used the human renin-producing cell line CaLu-6. Endogenous or pharmacological PPAR agonists (unsaturated fatty acids and thiazolidinediones, respectively) stimulated renin gene expression. Surprisingly, we found that PPAR targets a palindromic repeat with a 3-bp spacer (Pal3) in the proximal human renin promoter. Thus, renin is the first gene described with a functional Pal3 sequence. PPAR agonists also stimulated renin gene expression in cultured native juxtaglomerular cells, which are the main source of renin in vivo. In summary, PPAR was identified as a novel intracellular mediator involved in the upregulation of renin transcription.

Key Words: basic science • gene expression/regulation • hypertension (kidney), renin • cell signaling

	Introduction

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Plasma renin is aspartyl protease, produced by the juxtaglomerular (JG) cells of the kidney. Renin is the rate-limiting factor of the renin-angiotensin-aldosterone-system, which is of fundamental importance to the regulation of blood pressure.¹ Therefore, the mechanisms involved in the control of the renin gene are extensively characterized. An enhancer sequence, which activates transcription in a position- and orientation-independent manner, was identified in the 5'-flanking region of the mouse renin gene.² The renin enhancer contains an 50-bp-long region, which attracts much attention because it is involved in the regulation of renin transcription by virtually all cues tested until now.^2–7 A direct repeat 5'-AGGTCA-3' was identified within the 50-bp enhancer sequence.⁷ This direct repeat is principally known as the hormone-responsive element (HRE), because it is the consensus DNA-binding site for the nuclear hormone receptor superfamily.⁸ The nuclear hormone receptors represent ligand-activated transcription factors, which are the intracellular docking stations for membrane-permeable bioactive substances, such as corticoids, retinoids, vitamin D3, thyroid hormones, and free fatty acids. Retinoic acid (vitamin A) was found to stimulate renin transcription through retinoic acid receptor- and retinoid X receptor (RXR)-.⁷ Mice lacking the vitamin D3 receptor have elevated renin mRNA levels, and vitamin D3 inhibits renin promoter activity.⁹ Thyroid hormone was also found to regulate renin transcription.¹⁰ On the other hand, aldosterone does not influence renin transcription but stabilizes renin mRNA.¹¹

Thus, peroxisome proliferator-activated receptors (PPARs) remained as the last nuclear hormone receptor subfamily, which has not been studied for its impact on renin transcription. Such an effect is feasible because PPARs bind to DNA as heterodimers with the retinoic acid receptors RXRs, which are known to activate renin transcription through the HRE sequence in the renin enhancer.^7,12

Although renin enhancer was first identified in mice, it is also conserved in humans.^13,14 Mouse and human enhancer sequences are highly homologous, including the HRE.¹⁴ Because the human renin enhancer is functionally almost unmapped, and because PPARs are relevant for the development of some human diseases, we studied the effect of PPARs on renin gene expression in the human renin-producing cell line CaLu-6.

	Methods

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An expanded Methods section is available in the data supplement available at http://hyper.ahajournals.org.

Cell Cultures and Chemicals
CaLu-6 cells (ATCC-HTB-56) were grown in Eagle’s minimal essential media supplemented with 10% FBS, sodium pyruvate, 100 U/mL of penicillin, 100 µg/mL of streptomycin, and 1% nonessential amino acids at 37°C in a humidified atmosphere containing 5% CO₂. The isolation of mouse JG cells is described in detail elsewhere.¹⁵ Fatty acids and forskolin were purchased from Sigma, and thiazolidinediones/glitazones (rosiglitazone, pioglitazone, troglitazone, ciglitazone, and MCC-555) and the PPAR antagonist GW9662 were from Cayman Chemical. The general inhibitor of transcription actinomycin D was from Calbiochem/Merck. All of the active substances were dissolved in dimethyl sulfoxide and were applied for 18 to 20 hours in general. Control cells were treated only with vehicle. Unless otherwise specified, fatty acids were applied at 250 µmol/L, forskolin at 10 µmol/L, actinomycin D at 4 µg/mL, GW9662 at 1 µmol/L, and thiazolidinediones at 10 µmol/L. To demonstrate the high specificity of the transcriptional effect, rosiglitazone was applied at 200 nmol/L in the reporter gene experiments.

Plasmids
The modified pGL3 vector (Promega) encoding firefly luciferase under the control of the minimal human renin promoter (bases –199 to +23 relative to the transcription starting site, hRenMin construct) was a generous gift from Dr Ralf Mrowka and Thomas Brinkmeier (Institut für Vegetative Physiologie, Charite, Berlin, Germany). The human renin enhancer HRE (5'-TGACCTGGCCATACTGGCCT-3', direct repeats are underlined) or the mutated human renin enhancer HRE (5'-TTTCCTGGCCATACTTTCCT-3', changed bases are in italics) was inserted in front of the minimal human renin promoter in the hRenMin vector by site-directed mutagenesis (QuikChange kit, Stratagene; constructs HRE-hRenMin and HREmut-hRenMin, respectively). The mutations in the context of the hRenMin vector and the resulting constructs are presented in the Table.

View this table: [in this window] [in a new window]   Table. Mutations in the Proximal Human Renin Promoter

Statistics
Experiments were carried out in triplicate with 3 samples per condition. Levels of significance were estimated by ANOVA, followed by the Student’s unpaired t test. P<0.05 was considered significant.

	Results

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PPAR Agonists Stimulate Renin Gene Expression
In preliminary experiments, we found that the capacity of free fatty acids to stimulate renin gene expression corresponds with their PPAR affinity and that pharmacological PPAR agonists from the glitazone (thiazolidinedione) family also stimulate renin gene expression (please see Figures S1 and S2). Therefore, we suggested that PPAR is involved in the stimulation of renin gene expression. To demonstrate that the effect of endogenous and pharmacological PPAR agonists is mediated by PPAR, we used the PPAR antagonist GW9662 (Figure 1). GW9662 modifies a conserved cysteine residue in the PPAR molecule, thus interfering with ligand binding but not with DNA binding or with the interaction with other transcription factors.¹⁶ Therefore, GW9662 does not affect the basal expression of typical PPAR-dependent genes but only their ligand-induced activation. Accordingly, GW9662 alone had no significant effect on the basal level of renin mRNA. When co-incubated with GW9662, rosiglitazone, linoleic acid, or oleic acid practically lost their ability to stimulate renin gene expression. GW9662 did not significantly influence the increase of renin mRNA induced by the adenylate cyclase activator forskolin. Altogether, the data presented in Figure 1 provide evidence that PPAR acts as a potent and specific activator of renin gene expression.

View larger version (25K): [in this window] [in a new window]   Figure 1. Effect of the PPAR inhibitor GW9662 (1 µmol/L) on the stimulation of renin gene expression by PPAR agonists (10 µmol/L of rosiglitazone [Rosi], 250 µmol/L of linoleic acid, and 250 µmol/L of oleic acid) or forskolin (10 µmol/L). Renin and ß-actin mRNAs were quantified by real-time PCR. Data are means±SEM, *P<0.01 vs control.

PPAR Stimulates the Transcription of the Renin Gene
Gene expression is controlled either at the transcriptional level or posttranscriptionally by affecting the stability of mRNA. We first tested whether PPAR affects the stability of renin mRNA in CaLu-6 cells. None of the PPAR agonists studied preserved its ability to stimulate renin gene expression in the presence of the transcriptional inhibitor actinomycin D (Figure 2). On the other hand, elevation of cAMP by forskolin in the presence of actinomycin D still increased the renin mRNA level, consistent with earlier findings that cAMP stabilizes renin mRNA in CaLu-6 cells (Figure 2).¹⁷ PPAR agonists also did not influence the cAMP level or renin mRNA half-life in CaLu-6 cells (control half time=7 hours; rosiglitazone-treated half time=6.9 hours; data not shown). Therefore, we assumed that PPAR targets the cis-regulatory sequences of renin gene to enhance its transcription. Rosiglitazone activated the transcription of a reporter gene driven by the human renin enhancer HRE sequence fused to the minimal human renin promoter (Figure 3A and 3B). To our surprise, a construct containing mutated HRE was activated to a similar extent (Figure 3B). These data suggest that the key target sequence of PPAR is within the minimal human renin promoter hRenMin. Consistently, rosiglitazone or oleic acid stimulated the activity of the hRenMin reporter construct in a PPAR-dependent fashion (Figure 3C). The hRenMin promoter fragment contains 2 putative PPAR-binding sites: a palindromic repeat with 3-bp spacer (Pal3 sequence) 5'-GGGTACcctTCACCC-3' in position –148 to –134 and an HRE-like sequence 5'-AGGGCAgAGCAGA-3' in position –66 to –54 relative to the transcription starting site (spacers are in lowercase).^18,19 Mutation of the Pal3 sequence decreased the basal activity of hRenMin (Figure 3D). In addition, PPAR was found to be involved in the regulation of basal renin expression (please see Figure S3). Base changes in the Pal3 motif abolished the stimulatory effect of rosiglitazone on hRenMin (Figure 3D). However, a mutation of the Pal3 sequence in the context of the HRE-hRenMin construct (which has higher basal activity compared with hRenMin) only tended to decrease its basal activity and just attenuated (but not abolished) the effect of the PPAR agonist (Figure 3E). These data suggested that the enhancer HRE could partially attain the function of the Pal3 motif. Mutation of the HRE-like sequence decreased the basal rate of reporter activity but did not change the rate of stimulation by rosiglitazone (Figure 3D). In control experiments, mutation of the CNRE motif located at –124 to –115, which is known to be targeted by cAMP, did not influence the effect of rosiglitazone (Figure 3D).²⁰ Thus, the Pal3 sequence at –148 to –134 appears to be targeted by PPAR.

View larger version (24K): [in this window] [in a new window]   Figure 2. PPAR agonists do not influence the stability of renin mRNA in CaLu-6 cells. Cells were pretreated for 2 hours with the transcriptional inhibitor actinomycin D (4 µg/mL), then oleic acid, linoleic acid (both applied at 250 µmol/L), rosiglitazone, or forskolin (both applied at 10 µmol/L) was added, and the cells were incubated for additional 20 hours. Control cells were treated with actinomycin D only. Renin and ß-actin mRNAs were quantified by real-time PCR. Data are means±SEM, *P<0.05 vs control.

View larger version (34K): [in this window] [in a new window]   Figure 3. PPAR targets a Pal3 sequence in the proximal human renin promoter. A, Schematic map of the reporter constructs used. Regulatory elements are shown as ellipses. Filled ellipses indicate mutation. B, Effect of rosiglitazone on the activity of HRE-hRenMin and HREmut-hRenMin reporter constructs. C, Rosiglitazone or oleic acid stimulate the activity of the hRenMin reporter in a PPAR-dependent manner. D and E, Effect of rosiglitazone on the activity of hRenMin, Pal3mut, HRE-like-mut, CNREmut, HRE-hRenMin, and HRE-Pal3mut reporter constructs. The HRE-Pal3mut construct represents the HRE-hRenMin vector-containing mutated Pal3 sequence. The relative basal activity of each construct (in percentage compared with hRenMin basal activity, which was set to 100%) is shown within (D) or above (E) the corresponding columns. Rosiglitazone was applied at 200 nmol/L to demonstrate the high specificity of the effect. Oleic acid was applied at 250 µmol/L. The PPAR inhibitor GW9662 was applied at 1 µmol/L. Data are means±SEM. RLA indicates relative luciferase activity. *P<0.05 vs corresponding control. #P<0.05 vs hRenMin control.

PPAR Binds to the Pal3 Proximal Renin Promoter Sequence
Using electrophoretic mobility-shift assay, we found that the human renin Pal3 sequence binds a single protein complex in nuclear extracts of CaLu-6 cells (Figure 4A, lane 2). This interaction was competed by the human renin Pal3 motif (Figure 4A, lanes 3 and 4) but not by mutated Pal3 (Figure 4A, lane 5). An anti-PPAR antibody caused the appearance of 2 supershifted complexes (Figure 4A, lane 7, the middle and the lower arrow), whereas a nonspecific antibody (anti-rabbit IgG) competed only marginally with the binding of the shifted protein complex (Figure 4A, lane 6). Both complexes supershifted by the anti-PPAR antiserum seemed to be specific, because they disappeared in the absence of nuclear extract (Figure 4A, lane 8). Anti-RXR antibody also caused a supershift, suggesting the presence of RXR in the protein complex bound to the human renin Pal3 motif (Figure 4A, lane 9, the upper arrow). Because RXR is the standard interaction partner for PPAR, it seems feasible to suggest that the 2 complexes supershifted by the anti-PPAR antibody contain PPAR as a homodimer and as a heterodimer with RXR. Moreover, the Pal3 sequence is known to bind PPAR homodimers.¹⁹ To identify the PPAR/PPAR and the PPAR/RXR dimers, we used nuclear proteins from cells treated with a nontargeting small interfering (si)RNA, PPAR-specific siRNA, and RXR-specific siRNA. Knockdown of PPAR or RXR diminished the intensity of the shifted band, thus confirming the presence of both nuclear receptors in the protein complex bound to the human Pal3 motif and the efficacy of the RNA interference (please see Figure S4). PPAR-specific siRNA, as well as RXR-specific siRNA, decreased the amount of the upper supershifted complex in the presence of anti-PPAR antiserum (Figure 4A, compare lane 10 with lanes 11 and 12, the middle arrow). Therefore, we concluded that this protein complex contains PPAR/RXR heterodimers. In contrast, the amount of the lower supershifted complex, which should contain PPAR/PPAR homodimers, increased in nuclear extracts of cells treated with PPAR-specific siRNA or RXR-specific siRNA (Figure 4A, compare lane 10 with lanes 11 and 12, the lower arrow; see also Discussion). In chromatin immunoprecipitation experiments, we found that anti-PPAR and anti-RXR antibodies enrich the precipitated fraction of a human renin promoter fragment, containing the Pal3 sequence at –148 to –134 (Figure 4B, compare lane 3 with lanes 4 and 5), whereas an antibody against a nonrelated transcription factor (anti-RelB, served as negative control) did not (Figure 4B, compare lane 3 with lane 6). Altogether the electrophoretic mobility-shift assay and the chromatin immunoprecipitation experiments provide evidence that PPAR and RXR physically interact with the human renin Pal3 sequence.

View larger version (27K): [in this window] [in a new window]   Figure 4. PPAR binds to the Pal3 human renin sequence. A, Nuclear proteins from control (untreated) or from CaLu-6 cells treated with nontargeting siRNA (siControl), PPAR-specific siRNA (siPPAR), or RXR-specific siRNA (siRXR) were probed with 33P-labeled human renin Pal3 sequence by electrophoretic mobility-shift assay. Unlabeled double-stranded oligonucleotide containing human renin Pal3 (cold hRen Pal3) was added to the samples in lanes 3 and 4 in 10- and 50-fold molar excess, respectively. Unlabeled double-stranded oligonucleotide containing mutated human renin Pal3 (cold hRen Pal3mut) was added to the sample in lane 5 in 50-fold molar excess. Two microliters of antibody were applied in lanes 6 to 12 as follows: in lane 6, nonspecific anti-rabbit antibody (Santa Cruz, anti-NS); in lanes 7, 8, 10, 11, and 12, anti-PPAR antibody (Active Motif); and in lane 9, anti-RXR antibody (Santa Cruz). NS indicates nonspecific. Arrows indicate the supershifted protein complexes. B, Anti-PPAR (Active Motif) and anti-RXR antibodies (Santa Cruz), but not anti-RelB antibody (negative control, Santa Cruz), enrich the precipitated fraction of the Pal3 human renin promoter sequence. The input sample (diluted 1:10) was not antibody precipitated and served as a positive control.

PPAR Stimulates Renin Gene Expression in Cultured Native Mouse JG Cells
Finally, we studied the effect of PPAR agonists on renin gene expression in primary cultures of native mouse JG cells (Figure 5). As with CaLu-6 cells, stearic acid only tended to increase renin mRNA abundance, whereas the PPAR agonists oleic acid or rosiglitazone significantly increased renin mRNA. This increase was abrogated by the PPAR inhibitor GW9662. GW9662 did not significantly influence the increase of renin mRNA induced by forskolin, indicating the specificity of the effect. The finding that PPAR stimulates renin gene expression in native JG cells suggests that PPAR could be important for the control of renin gene in vivo.

View larger version (24K): [in this window] [in a new window]   Figure 5. The PPAR agonists rosiglitazone (10 µmol/L) and oleic acid (250 µmol/L) stimulate renin gene expression in cultured native mouse JG cells. Stearic acid (250 µmol/L) was used as negative control, whereas forskolin (10 µmol/L) was used as positive control. The PPAR inhibitor GW9662 was applied at 1 µmol/L. Renin and ß-actin mRNA were quantified by real-time PCR. Data are means±SEM; *P<0.05 vs control.

	Discussion

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In this study, we provide experimental evidence in favor of the hypothesis that PPARs are involved in the control of renin gene expression. We predicted a role for PPARs in the regulation of renin gene expression using a molecular approach. There was strong initial evidence supporting such a role.^7,12 A functional DNA-binding site, similar to the consensus motif for PPARs, was detected in the conserved 5'-renin gene enhancer. The retinoic acid nuclear receptor RXR, which is the typical interaction partner for PPARs, binds to the mouse renin gene enhancer. Lastly, vitamin A, which is the natural ligand of RXRs, was found to stimulate the transcription of the renin gene.

Renin gene expression is upregulated by cAMP in CaLu-6 cells through stabilization of renin mRNA, although transcriptional mechanisms are also involved.^17,21 We provided several lines of evidence that PPAR stimulates renin gene expression without affecting the stability of renin mRNA (Figures 1, 2, and 5; data not shown). First, the effect of PPAR agonists was abolished when transcription was generally inhibited by actinomycin D. Second, the PPAR ligands did not increase intracellular cAMP, which is known to stabilize renin mRNA. Third, the PPAR antagonist GW9662 did not significantly affect the increase of renin gene expression induced by cAMP. After we ruled out the possibility that PPAR may stabilize renin mRNA, we studied the transcriptional mechanisms responsible for the PPAR-induced increase of renin gene expression.

A very unexpected finding, which partially contradicted our initial hypothesis, was that the renin enhancer HRE is dispensable for the regulation of renin transcription by PPAR. These data fit with recent evidence challenging the role of the renin enhancer in the regulation of renin expression in vivo.²² On the other hand, the mouse renin enhancer was shown to be critical for the salt-dependent control of renin synthesis in transgenic mice.²³ Thus, the role of the renin enhancer in the regulation of renin gene expression in vivo remains to be further clarified.

We identified a Pal3 motif in the minimal human renin promoter as a PPAR-binding sequence and renin as the first gene with a functional Pal3 regulatory element (Figure 3). The canonical PPAR DNA-binding site represents a hexamer direct repeat (5'-AGGTCA-3') with 1-bp spacing (DR1), which binds the PPAR/RXR heterodimer.¹² The palindromic repeat sequence with 3 spacer bases 5'-(A/G)GGTCAcngTGACC(C/T)-3' (Pal3) was identified as a DNA target motif for PPAR homodimers in a PCR-mediated random site selection with in vitro translated proteins.¹⁹ The human renin promoter Pal3 sequence differs from the canonical Pal3 site by only 2 inverted bases in the 5'-repeat (CAAC) and a single base in the spacer (TG). However, these changes do not prevent the binding of PPAR (Figure 4). Our results suggest that the Pal3 sequence is sufficient for the PPAR-dependent regulation of the human renin gene. The Pal3 motif resides in a region that is highly conserved in human, mouse, and rat renin genes.²⁴ It remains to be clarified whether the mouse and rat homologues of the human Pal3 sequence have similar function. We could not exclude the possibility that there are further PPAR target sites upstream from the minimal 5'-renin gene promoter. Moreover, the enhancer HRE was found to compensate to some extent for the absence of a functional Pal3 sequence (Figure 3E).

The anti-PPAR antibody supershifted 2 separate protein complexes, which seemed to contain PPAR/RXR heterodimers or PPAR/PPAR homodimers bound to the human renin Pal3 motif (Figure 4A). As expected, knockdown of PPAR or RXR diminished the bound amount of PPAR/RXR heterodimer complex but surprisingly increased the binding of the protein complex, which should contain the PPAR/PPAR homodimer. On the basis of the unique feature of the Pal3 motif to bind both PPAR/RXR and PPAR/PPAR, this paradox was already predicted.¹⁹ Because RXR forms heterodimers with many nuclear receptors, it is very likely that its amount in the cell is limiting. Therefore, if RXR is knocked down, the formation of PPAR/PPAR homodimers would be enhanced. On the other hand, PPAR should compete with other nuclear receptors for RXR. Consequently, knockdown of PPAR would reduce its capacity to compete for RXR and would paradoxically result in enhanced formation of PPAR/PPAR homodimers.

We could not detect any protein binding to the HRE-like sequence by electrophoretic mobility-shift assay (data not shown). The HRE-like sequence overlaps with a sequence which putatively binds HMG "architectural" transcription factors (at –80 to –64).²⁵ The HMG proteins are nonhistone chromosomal proteins, which bind with low specificity to their DNA target to facilitate transcription. Therefore, it could be suggested that impaired binding of HMG could have resulted in decreased basal activity of the construct with the overlapping mutated HRE-like region (Figure 3D).

Perspectives
In the present article we report that the nuclear receptor PPAR stimulates renin transcription acting through a Pal3 sequence. This effect of PPAR could be of interest for the improved understanding of the pathogenesis of arterial hypertension in obese patients with metabolic syndrome. These patients have increased renin production as a rule, and whether PPAR contributes to this increase is a matter of controversy. Thus, glitazones have a hypotensive effect in obesity, and a dominant-negative mutation of PPAR results in hypertension.^26,27 In contrast, PPAR knockout results in hypotension, which importantly is not accompanied by increased renin gene expression.²⁸ Our results suggest that PPAR activation stimulates renin transcription in the renin-producing CaLu-6 cells. We are currently generating mice with a kidney-specific knockout of PPAR to characterize the effect of PPAR on renin gene expression in vivo.

	Acknowledgments

 
We thank Dr Jürgen Schnermann for critically reading the article.

Source of Funding

This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 699, Project B1.

Disclosures

None.

Received April 22, 2007; first decision May 10, 2007; accepted August 7, 2007.

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