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(Hypertension. 2005;45:3.)
© 2005 American Heart Association, Inc.

Brief Review

Transcriptional Regulation of Renin

An Update

Li Pan; Kenneth W. Gross

From the Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY.

Correspondence to Dr Kenneth W. Gross, Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263-0001. E-mail gross{at}acsu.buffalo.edu

	Abstract

Top Abstract Introduction The Proximal Promoter Region The Enhancers References

 
Renin, as a component of the renin-angiotensin system, plays important roles in the regulation of blood pressure, electrolyte homeostasis, and mammalian renal development. Transcription of renin genes is subject to complex developmental and tissue-specific regulation. Progress has been made recently in elucidating the molecular mechanisms involved in renin gene expression. Using mouse As4.1 cells, which have many features characteristic of the renin-expressing juxtaglomerular cells of kidney, a proximal promoter region (–197 to –50 bp) and an enhancer (–2866 to –2625 bp) have been identified in the mouse renin gene, Ren-1^c, that are critical for its expression. The proximal promoter region contains at least 7 transcription factor-binding sites, including a binding site for the products of Hox, developmental control genes. The enhancer consists of at least 11 transcription factor-binding sites and is responsive to various signal transduction pathways, including cAMP, retinoic acid, endothelin-1, and cytokines, to alter renin mRNA levels. Sequence highly homologous to the mouse enhancer is also found in the human and rat renin genes. How these regulatory regions function in vivo will be the focus of future study.

Key Words: renin • transcription

	Introduction

Top Abstract Introduction The Proximal Promoter Region The Enhancers References

 
The renin-angiotension system (RAS) has long been recognized to play a critical role in blood pressure homeostasis and electrolyte balance. More recently, it has become evident that a functional RAS is required for normal mammalian renal development.¹ Renin, an aspartyl protease, initiates an enzymatic cascade that results in the production of the vasoactive peptide angiotensin II, the major effector molecule of the RAS. Transcription of renin genes is tissue-specifically and developmentally regulated.² The principle source of active renin in the circulation is the kidney. In the mouse kidney, renin expression is first detected at 14.5 days of gestation in the earliest developing arteries, and is then found in the newly forming arterial branches as the renal arterial tree develops. Subsequently, renin expression is progressively restricted to smaller arteries and arterioles until, in the adult, it is abundantly expressed in juxtaglomerular cells located in the wall of the afferent arteriole. A number of other tissues also express renin genes in mice, including submandibular gland, adrenal gland, testes, ovary, anterior prostate, brain, and fetal subcutaneous tissue.

Results from transgenic studies have shown that 4 kb of the mouse renin 5' flanking sequence is sufficient to specify correct renin expression patterns in mouse embryonic, extra-embryonic, and adult tissues using SV40 T antigen or GFP as reporters, suggesting that the most important regulatory regions reside within this region.^3,4 Availability of these transgenic lines has allowed us to isolate a renin-expressing kidney tumor cell line (As4.1)⁵ and apply fluorescence-activated cell sorting (FACS) to acquire natural renin-expressing cells, valuable for identifying cis-acting elements and trans-acting factors important for renin gene expression. As4.1 cells have many features characteristic of juxtaglomerular cells in the kidney, including expression of high levels of renin mRNA, presence of renin-containing dense granules, and secretion of active renin protein. In addition, primary cultures of chorionic cells,⁶ and Calu-6 cells⁷ developed from a pulmonary carcinoma, have been found to express endogenous renin and are widely used to study the transcriptional regulation of the human renin gene.

	The Proximal Promoter Region

Top Abstract Introduction The Proximal Promoter Region The Enhancers References

 
The HOX · PBX-Binding Site
Using nuclear extracts prepared from As4.1 cells, we showed in electrophoretic mobility shift assays (EMSA) the binding of nuclear proteins to the mouse renin (Ren-1^c) promoter region from –72 to –50, which is critical for Ren-1^c expression.⁸ Further competition assays demonstrated that the nucleotides sufficient for binding are TAATAAATCA (or inverting TGATTTATTA), which is highly conserved among the human, rat, and mouse renin genes and a precise match to the consensus binding sequence for PBX and HOX 6 to 10 paralog members (TGATTTATNN).⁹

HOX proteins belong to the family of homeodomain-containing transcription factors and play critical roles in specifying positional information along several embryonic axes.¹⁰ In vertebrates, there are 39 Hox genes organized in 4 clusters (A, B, C, and D) on separate chromosomes, with members of each cluster classified into as many as 13 paralog groups based on sequence similarity. HOX proteins can bind DNA as monomers or heterodimers with another homeodomain protein PBX on the HOX · PBX recognition sequence. Moreover, homeodomain protein MEIS or its homolog PREP1 has been shown to interact with PBX.¹¹ This interaction is essential for PBX nuclear translocation. Furthermore, a HOX · PBX · MEIS/PREP1 ternary complex has been found to bind at the HOX · PBX recognition sequence to regulate several HOX-responsive genes.¹²

Members from HOX paralog groups 6 to 10 including HOXB6, HOXB7, HOXC8, HOXB9, and HOXD10 were synthesized in vitro and analyzed in EMSA to test whether they could bind to Ren-1^c promoter sequence in the presence or absence of PBX1b.¹³ Results show that HOX9/10 paralog members can pair with PBX1b and bind to the Ren-1^c HOX · PBX site with high affinities. PREP1 has also been shown to form a ternary complex with HOX and PBX on the Ren-1^c promoter (Figure 1 for cis-regulatory elements identified within the Ren-1^c 5' flanking sequence). Moreover, mutational analysis shows that both the HOX and PBX half-sites are essential for Ren-1^c expression, because a point mutation in either half-site completely abrogates the binding of the HOX · PBX complex and dramatically reduces transcriptional activity of the Ren-1^c gene in As4.1 cells.

View larger version (17K): [in this window] [in a new window]   Figure 1. Schematic representation of transcription factor-binding sites within the Ren-1c 5' flanking sequence. Shown are identified transcription factor-binding sites within the proximal promoter (Pa-Pi) and the enhancer (Ea-Ek). Transcription factors binding to these sites are labeled as described in the text. Unidentified transcription factors are labeled with a question mark (?).

These observations strongly suggest that the renin gene is an immediate downstream target of class I Hox gene regulation. Thus, the generation of angiotensin II, a hormone with known growth factor activities, as well as pressor activity, is directly regulated by an important set of developmental control genes that govern embryonic patterning. This intriguing correlation underlies the emerging realization of the roles played by RAS during development and in pathophysiology.

Tamura et al¹⁴ have shown that the protein product of the retinoblastoma susceptibility gene, RB, increases Ren-1^c promoter activity in human embryonic kidney cells, which do not express endogenous renin. Their results suggest that the induction by RB is mediated through the sequence from –75 to –47, which corresponds to the HOX · PBX-binding site. It will be interesting to test whether RB can interact directly with the HOX complex to regulate renin gene expression. The HOX · PBX-binding site has also been shown to be involved in directing the cAMP response of the mouse or human renin promoter.^15,16 The HOX · PBX complex appears necessary for cAMP responsiveness, if not sufficient, because it has been reported that PKA can activate transcription mediated by the HOX · PBX complex by recruiting the CREB-binding protein.¹⁷

Functional Cooperation Between HOX · PBX and Other Transcription Factors Binding to the Proximal Promoter of the Ren-1^c Gene
In addition to the HOX · PBX-binding site, there are other important transcriptional factor-binding sites within the proximal region of the Ren-1^c gene.¹⁸ Deletion of the region from –197 to –70, which is located immediately 5' to the HOX · PBX-binding site, in a construct containing 4.1 kb of the Ren-1^c 5' flanking sequence reduced transcriptional activity of the Ren-1^c promoter by 99% in As4.1 cells. Six cis-acting elements have been identified in this region (Figure 1). Two NFI-binding and an Sp1/Sp3-binding site lie within the distal portion of the region (–197 to –103). Mutation of these sites resulted in a 90% decrease in Ren-1^c promoter activity. Three other sites, Pb, Pc, and Pd, which contain nucleotide motifs CCTG, CCAC, and AAAACAGGCT, respectively, are located between –103 and –69. Each of these sites binds nuclear proteins and contributes significantly to high-level renin expression in As4.1 cells. Results from mutational analysis of these transcription factor-binding sites suggest a functional cooperation between the HOX · PBX-binding site and Pb/Pc. The identities of transcription factors binding at Pb and Pc are as yet unknown.

All the transcription factor-binding sites except Pb identified within the Ren-1^c proximal promoter region from –197 to –69 are located within the M3 insertion region (–564 to –80) (Figure 2), which is not present in the human or rat renin promoter. Thus, binding of these transcription factors may provide the mouse renin promoter higher transcriptional activity compared with the human or rat promoter, in agreement with higher circulating levels of renin in mice than those in humans or rats.

View larger version (66K): [in this window] [in a new window]   Figure 2. Alignment of the proximal regions of the human, rat, and mouse renin genes. Sequences of the human, rat, and mouse Ren-1c proximal promoters are aligned using multiple Sequence Alignment in Vector NTI (InforMax, Inc). cis-Regulatory elements (A to F) identified in the human promoter are shown in boldface. The sequence of the M3 insertion (–564 to –80) within the Ren-1c promoter is not included in the alignment and its position is indicated by an arrow. The putative CBF1-binding sites are boxed.

cis-Regulatory Elements Within the Proximal Region of the Human Renin Promoter
Using primary culture of human chorionic cells as a model system, Borensztein et al¹⁹ have identified 6 transcription factor-binding sites (A–F; Figure 2) within the proximal promoter region of the human renin gene. Site A contains a TATA box and an Ets-binding site, whereas site B is a HOX · PBX-binding site. It has been shown that site D contains a cAMP-responsive element (CRE), which binds several transcription factors including CREB and ATF1 in renin-expressing Calu-6 cells.²⁰ Site E contains a putative binding site for ARP-1 (COUP-TFII), a member of the orphan steroid receptor superfamily. Transcription factors binding to sites C and F are yet to be identified. The HOX · PBX-binding site and CRE have been demonstrated to be important for both basal and cAMP-induced promoter activity of the human renin gene in human chorionic cells.¹⁶ However, whether the Ets-binding site and sites C, E, and F contribute to promoter activity of the human renin gene has not been determined. Moreover, it will be interesting to determine whether these transcription factor-binding sites are present in the rat or mouse renin promoter, because the alignment of human, rat, and mouse proximal promoter sequences reveals strong sequence conservation (Figure 2).

The Notch Signaling Pathway
By comparison of the human, rat, and mouse renin proximal promoter sequences, we have identified a highly conserved sequence homologous to the recognition sequence for CBF1 [RBP-J/Su(H)/LAG1] (Figure 2), a nuclear effector of the Notch signaling pathway. Notch is a transmembrane receptor that mediates cell–cell communication to determine cell fates and regulate pattern formation.²¹ On activation of Notch by binding its ligand, the intracellular domain of Notch (NIC) is released by proteolytic cleavages, translocates to the nucleus, and subsequently binds transcription factor CBF1 to activate gene expression. Binding of NIC turns CBF1 from a repressor to an activator by replacing the CBF1-bound co-repressor complex with a co-activator complex.

Results from EMSA have shown that nuclear proteins binding to the putative rat or mouse CBF1 recognition sequence contain CBF1 (2004, Pan and Gross, unpublished results). Further study has shown that NIC can activate transcription from a promoter containing multiple copies of the rat renin CBF1-binding site. Finally, we have shown that NIC can cooperate with Ets1 or HOXD10 · PBX1b · PREP1 to activate the proximal promoter of rat renin. The identification of renin genes as the downstream target of the Notch signaling pathway will facilitate the understanding of mechanisms involved in tissue-specific and developmental regulation of renin gene expression.

The LXR-Binding Site
Dzau et al have identified a CNRE (an overlapping CRE and a negative responsive element) at –600 bp of the mouse renin promoters.²² They have proposed that competition between the negative responsive element-binding protein and the CRE-binding proteins for binding to the CNRE is responsible for tissue-specific expression of the mouse renin gene. They further suggest that the reason that a duplicated copy of the renin gene, Ren-2, found in some strains of mice, is strongly expressed in the submandibular gland is that there is an M2 element inserted immediately upstream of the CNRE. Thus, the NRE is not functional in the Ren-2 promoter.²³ However, results from analysis of the sequences and expression profiles of natural renin gene variants found in the closely related mouse species Mus hortulanus argue against this.²⁴ This species also expresses high levels of the Ren-2 gene in the submandibular gland and contains the same sequence elements present in the DBA/2 Ren-2 allele, including the NRE, but does not have the M2 insertion.

A recent report by the same group shows that LXR, a member of the nuclear receptor superfamily, binds to the CNRE and mediates the cAMP response of the mouse renin promoter.²⁵ LXR was isolated from a DBA/2J mouse kidney cortex library as a CNRE-binding protein by the yeast one-hybrid system. However, LXR expression was not observed in As4.1 cells. Dzau et al postulate that LXR expression was lost from As4.1 cells during their establishment in culture, leading to a lack of cAMP responsiveness of renin expression in these cells. When an LXR expression vector was overexpressed in As4.1 cells, transcriptional activity of a reporter construct containing the CNRE was induced by cAMP treatment. Recently, we have initiated expression profiling of the natural renin-expressing cells isolated from Ren-GFP transgenic mice by FACS. These FACS-isolated cells appear to have a very low level of LXR expression, as judged by Affymetrix microarray assays, real-time polymerase chain reactions, and massively parallel signature sequencing (2004, Jones, Glenn, and Gross, unpublished results). Thus, whether LXR regulates renin expression in vivo requires further investigation.

	The Enhancers

Top Abstract Introduction The Proximal Promoter Region The Enhancers References

 
The Renal Enhancer
A 242-bp element (–2866 to –2625 bp) has been identified in the Ren-1^c 5' flanking sequence in As4.1 cells to act as a classic enhancer.⁸ The Ren-1^c enhancer is capable of stimulating promoter activity by >50-fold in an orientation-independent fashion. Eleven transcription factor-binding sites have been identified within the enhancer in As4.1 cells. Among these sites, a CRE and an adjacent E-box are most critical in providing basal expression of the Ren-1^c gene.²⁶ Mutation of either element in a construct containing 2866 bp of the Ren-1^c 5' flanking sequence results in almost complete loss of enhancer activity. EMSA analysis indicates that transcription factors CREB/CREM and USF1/USF2 bind at the CRE and the E-box, respectively. The CRE is capable of responding to the forskolin (an activator of adenynyl cyclase) treatment by increasing transcriptional activity in JEG-3 cells, but does so only minimally in As4.1 cells. We have hypothesized that the cAMP pathway in As4.1 tumor cells may be constitutively active under basal conditions. Treatment of As4.1 cells with the PKA inhibitor H-89 reduces the Ren-1^c mRNA level, and this inhibitory effect is specifically mediated by the CRE within the Ren-1^c enhancer. Because As4.1 cells were selected from tumors initiated by transgene-targeted oncogenesis with a Ren promoter driving SV40 T antigen, it is possible that a cellular mutation arose in the cAMP pathway, facilitating maximal stimulation of the enhancer. Klar et al²⁷ have shown that forskolin is capable of activating renin expression in As4.1 cells only in the presence of IBMX, an inhibitor of cAMP-phosphodiesterases (PDE). They have also shown that high-level expression of PDE-3 and PDE-4 contributes to high PDE activity in As4.1 cells.

Two TGACCT motifs, which are separated by 10 bp and homologous to the steroid receptor-binding site, are located downstream of the E-box in the Ren-1^c enhancer. Sigmund et al have identified retinoic acid receptors/retinoic X receptors as transcription factors binding to these 2 sites.²⁸ Binding of retinoic acid receptors/retinoic X receptors in As4.1 cells stimulates not only basal enhancer activity but also the retinoic acid induction of Ren-1^c expression. The nuclear orphan receptor EAR2 has also been shown to bind to the TGACCT motifs.²⁹ However, it regulates Ren-1^c expression negatively in As4.1 cells. Recent studies by Li et al³⁰ demonstrated that both renin mRNA and protein levels in the kidney are dramatically increased in vitamin D receptor-null mice. Further study indicates that treatment of As4.1 cells with vitamin D results in decrease in promoter activity of a transfected reporter construct containing 4.1 kb of the Ren-1^c 5' flanking sequence. It was demonstrated earlier by Sigmund et al that 1,25-dihydroxyvitamin D₃ was able to repress transcriptional activity of a construct containing 3 copies of the TGACCT-N₁₀-TGACCT element placed upstream of a Ren promoter.²⁸ Thus, the TGACCT elements within the renin enhancer appear to be the putative vitamin D receptor-binding sites. We have identified several additional candidate nuclear orphan receptors that are highly expressed in FACS-sorted natural renin-expressing cells isolated from Ren-GFP transgenic mice. Whether these proteins can bind to the TGACCT motifs and regulate renin expression will be tested directly.

An NF-Y–binding site has been located close to the 3'-end of the enhancer, which overlaps with the downstream TGACCT motif.³¹ Mutation of the NF-Y site increases enhancer activity, demonstrating that NF-Y is a negative regulator of renin transcription. Results from EMSA suggest that the binding of NF-Y may prevent the binding of transcription factors to the TGACCT motif and, as a result, inhibit enhancer activity.³²

Six additional transcription factor-binding sites have been identified within the distal portion (–2866 to –2699) of the enhancer, including 4 NFI-binding, an Sp1/Sp3-binding, and an unknown transcription factor-binding site.³³ Mutational analysis has demonstrated that each of these binding sites contributes to overall enhancer activity, whereas mutations of all 6 sites result in a 90% decrease in Ren-1^c expression. NFIX, the product of 1 of 4 homologous NFI genes, is the predominant NFI mRNA expressed in As4.1 cells, strongly suggesting a critical role of NFIX in regulating renin gene expression. Moreover, a direct interaction between NFIX and Sp1 has been reported.³⁴ It seems that the cooperation between these 2 proteins is important for renin transcription because both the enhancer and the proximal promoter of the Ren-1^c gene contain adjacent NFI-binding and Sp/Sp3-binding sites.^18,33

Transcription of the Ren-1^c gene has been shown to be downregulated by endothelin-1,^18,35 angiotensin II,³⁶ mechanical stretch,³⁷ and inflammatory cytokines.^38–40 To understand the mechanisms involved in these negative regulations, we have analyzed in detail the regulation of Ren-1^c expression by cytokines such as oncostatin M, IL-6, and IL-1ß, all of which have been shown to inhibit renin gene expression.⁴¹ The Ren-1^c enhancer has been identified as the target sequence for the inhibition by these cytokines. It appears that a 39-bp segment within the enhancer containing the CRE, the E-box, and the upstream TGACCT element is sufficient for the inhibition induced by IL-1ß. However, mutation of each of the 3 component sites does not abolish the inhibitory effect. The same region is also critical, but not sufficient, for the inhibition mediated by oncostatin M and IL-6. These data suggest that the direct target of the associated cytokines may be co-activators interacting with the transcription factors binding at the enhancer. Moreover, the extracellular signal-regulated kinase signaling pathway has been shown to be involved in the inhibition of renin gene expression by all 3 cytokines. Todorov et al⁴² have studied the inhibition of Ren-1^c gene expression by tumor necrosis factor-. They suggest that the inhibition is mediated by the CRE within the enhancer. They have further shown that transcription factor NFB, which is activated by tumor necrosis factor- treatment, can form a complex with proteins binding to the CRE. However, we have found that mutation of the CRE does not significantly affect the inhibitory effect induced by IL-1ß, which can also activate the NFB pathway.⁴¹ Moreover, an inhibitor of the NFB pathway, 1-pyrrolidinecarbodithioic acid, only minimally reduces the IL-1ß inhibition of transcriptional activity of a transfected construct containing Ren-1^c enhancer placed upstream of a Ren-1^c promoter in As4.1 cells. Further investigation is needed to understand the mechanisms involved in the inhibition of renin transcription induced by inflammatory cytokines.

An element highly homologous to the mouse renin enhancer has also been found in the human and rat 5' flanking sequences. The human enhancer is located 11 kb upstream of the transcriptional start site and shows 71% identity with the mouse enhancer,^31,43 whereas the rat enhancer is located at –5868 to –5615 bp and is 85% homologous to the mouse enhancer. Results from transfection studies demonstrate that activity of the rat or human enhancer is much weaker than that of the mouse counterpart (more information can be found in an online supplement available at http://www.hypertensionaha.org). Sequence comparisons and EMSA analysis have revealed that 2 NFI-binding sites are not present in either the human or the rat enhancer, whereas the Sp1/Sp3-binding site is absent in the rat enhancer (2004, Pan and Gross, unpublished results). Because the cooperation between NF1-binding and Sp1/Sp3-binding sites is important for activity of the distal portion of the mouse enhancer,³³ lack of Sp1/Sp3-binding and 2 NFI-binding sites may explain the ineptness of the rat distal enhancer in contributing to enhancer activity. Moreover, both human³¹ and rat proximal enhancers show weaker transcriptional activity compared with the corresponding mouse region because of the absence of the downstream TGACCT motif. Mutation of these enhancers in vivo will provide valuable insights into their roles in regulating renin gene expression.

The Chorionic Enhancer
Germain et al⁴⁴ have identified a region (–5777 to –5552) in the human renin 5' flanking sequence capable of activating a human renin promoter or a heterologous promoter by 60-fold in an orientation-independent fashion in primary cultures of human chorionic cells. This enhancer shows much less activation in As4.1 or Calu-6 cells and no activation in nonrenin-expressing cells, suggesting that it is chorion-specific. Results from DNase I footprinting assays demonstrate that there are 3 transcription factor-binding sites within the chorionic enhancer. However, the identities of these transcription factors are as yet unknown. Whether such an enhancer is present in the mouse or rat renin 5' flanking sequence remains to be investigated.

Perspectives
A number of cis-acting elements important for regulation of the renin genes have been identified using renin-expressing cell lines. However, whether they are important for renin expression in vivo is still unknown. We have developed transgenic mice expressing GFP under the control of the Ren-1^c 5' flanking sequence contained in a large bacterial artificial chromosome (88K7-GFP). Transgene expression from bacterial artificial chromosomes has frequently been observed to be less subject to position effect. Site-directed mutations are being introduced into 88K7-GFP using the homologous recombination methodology to test directly in vivo the repertoire of putatively important cis-regulatory elements. Moreover, the putative transcription factors binding to these cis-acting elements will be identified by comparing the expression profile of As4.1 cells with that of FACS-sorted green cells isolated from 88K7-GFP transgenic mice. Finally, RNAi methodology and mice deficient for specific protein expression will be used to functionally test the regulatory roles of the putative transcription factors identified.

	Acknowledgments

 
We thank Dr Craig A. Jones for critical reading of the manuscript. The authors’ research is supported by National Institutes of Health grant HL48459 (to K.W.G.) and funds from the Bruce Cuvelier Family, and used core facilities supported in part by Roswell Park Cancer Institute’s National Cancer Institute-funded Cancer Center support grant CA-16056.

Received September 24, 2004; first decision October 1, 2004; accepted October 26, 2004.

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37. Ryan MJ, Black TA, Gross KW, Hajduczok G. Cyclic mechanical distension regulates renin gene transcription in As4.1 cells. Am J Physiol Endocrinol Metab. 2000; 279: E830–E837.[Abstract/Free Full Text]
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