Evaluating a Model of an NRE Mediated Tissue-Specific Expression of Murine Renin Genes

Abonia, J. Pablo; Howles, Philip N.; Abel, Kenneth; Black, T. Andrew; Jones, Craig; Gross, Kenneth W.

doi:10.1161/01.hyp.37.1.105

Cited by 6 publications

(5 citation statements)

References 16 publications

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“…23 This notion has been chal- lenged by experiments examining renin expression in wildderived mice 24 and by comparative sequence analysis. 25 Recently, Gross and colleagues 4 have reported that the Abd-class of Hox genes also binds to this region and plays a major role in regulating the renin gene. Like other targets of Hox transcription factors, expression of renin exhibits a very specific temporal and spatial profile during fetal development.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Nuclear Orphan Receptor (Ear2) as a Negative Regulator of Renin Gene Transcription

Liu

Huang

Sigmund

2003

Circulation Research

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Abstract-A potent transcriptional enhancer was previously identified upstream of the mouse renin gene. Within the enhancer is a TGACCT direct-repeat motif, required for enhancer activity, that is the consensus sequence recognized by members of the thyroid hormone subfamily of steroid hormone receptors. We previously reported that RAR/RXR bind to this sequence and mediate the induction of renin promoter activity by retinoids. However, gel mobility shift assays clearly show that other as yet unidentified factors also bind to this motif. In order to identify some of these TGACCT binding factors, we screened a yeast one-hybrid cDNA library derived from mouse As4.1 cells. One of these encoded the orphan nuclear receptor Ear2. Recombinant Ear2 was purified from Escherichia coli and an antipeptide antisera was generated. EMSA showed that purified recombinant Ear2 specifically binds the TGACCT direct-repeat motif. Transfection assays showed that Ear2 potently decreases both baseline and retinoid-induced mouse renin promoter activity in a dose-dependent, enhancer-dependent, and sequence-specific manner. Mutations in Ear2, which abolish its binding to the TGACCT motif, also abolish transcriptional repression. Ear2 was identified as a nuclear protein in As4.

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Section: Discussionmentioning

confidence: 99%

Identification of a Nuclear Orphan Receptor (Ear2) as a Negative Regulator of Renin Gene Transcription

Liu

Huang

Sigmund

2003

Circulation Research

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“…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.…”

Section: The Lxr␣-binding Sitementioning

confidence: 96%

Transcriptional Regulation of Renin

Gross

2005

Hypertension

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Abstract-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 (Ϫ197 to Ϫ50 bp) and an enhancer (Ϫ2866 to Ϫ2625 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 Ⅲ transcription T he 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 tissuespecifically 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 Ϸ4 kb of the mouse renin 5Ј flanking sequence is sufficient to specify correct renin expression patterns in mouse embryonic, extraembryonic, 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 transactin...

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“…The promoter sequences of mut CNRE Ren-1 C and Ren-2 are not exactly the same (31); the lack of obvious phenotype in the Ren-1 C BAC TgM carrying mut CNRE might be attributed to this difference. In apparent conflict with the proposed model, however, it has been reported that the Ren-2 allele of the Mus hortulanus strain produces abundant Ren-2 mRNA in the SMG, even though its promoter has no insertion next to the NRE (31). Therefore, the mechanism by which locus-specific differences of renin gene expression are achieved in the SMG and kidney remains an open question.…”

Section: Discussionmentioning

confidence: 89%

A single nucleotide mutation in the mouse renin promoter disrupts blood pressure regulation

Tanimoto¹,

Sugiura²,

Kanafusa³

et al. 2008

J. Clin. Invest.

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Renin, a major regulatory component of the renin-angiotensin system, plays a pivotal role in regulating blood pressure and electrolyte homeostasis and is predominantly expressed in the kidney. Several cAMP-responsive elements have been identified within renin gene promoters. Here, we study how 2 such elements, renin proximal promoter element-2 (RP-2) and overlapping cAMP and negative regulatory elements (CNRE), affect the transcriptional regulation of renin. We generated Tg mice (TgM) bearing BACs containing either WT or mutant RP-2 or CNRE, integrated at single chromosomal loci. Analysis of the TgM revealed that RP-2 was essential to basal promoter activity in the kidney, while renin mRNA levels did not significantly change in any tissues tested in the CNRE mutant TgM. To evaluate the physiological significance of these mutations, we used the BAC Tg to rescue hypotensive Renin-null mutant mice. As predicted, no renin expression was observed in the kidneys of RP-2 mutant/Renin-null compound mice, whereas renin expression in CNRE mutant compound mice was indistinguishable from that in control mice. Consistent with this, RP-2 mutant animals were hypotensive, while CNRE mutants had normal blood pressure. Thus, transcriptional regulation of renin expression via RP-2 but not CNRE is critical for blood pressure regulation by this gene. IntroductionRenin is an aspartyl protease synthesized mainly in the juxtaglomerular (JG) cells of the kidney. It catalyzes cleavage of a unique substrate, angiotensinogen, a plasma protein synthesized predominantly in the liver; cleavage yields the decapeptide angiotensin I (AI). AI is further processed by angiotensin-converting enzyme to produce the octapeptide angiotensin II (AII), which mediates vasoconstriction and aldosterone secretion through angiotensin receptors (ATs), leading to increased BP. Renin catalyzes the first, rate-limiting reaction of the renin-angiotensin system and thus plays a central role in regulating overall activity of the renin-angiotensin system. Our lab and others have shown by gene ablation in the mouse that renin is essential to BP homeostasis (1, 2).A number of physiological stimuli, such as renal sympathetic activity, sodium depletion, and low BP, induce renin transcription and secretion in order to maintain BP homeostasis. Several of these stimuli utilize cAMP as an intracellular signal (reviewed in ref.3). In JG cells, noradrenalin released from sympathetic nerve endings activates adenylate cyclase. Intracellular cAMP concentration in JG cells can also be modified directly or indirectly by low distal tubular salt load, increased NO and prostaglandins, and/or decreased adenosine release from the macula densa. Pharmacological blockade of AII synthesis or receptor function also increases

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Evaluating a Model of an NRE Mediated Tissue-Specific Expression of Murine Renin Genes

Cited by 6 publications

References 16 publications

Identification of a Nuclear Orphan Receptor (Ear2) as a Negative Regulator of Renin Gene Transcription

Identification of a Nuclear Orphan Receptor (Ear2) as a Negative Regulator of Renin Gene Transcription

Transcriptional Regulation of Renin

A single nucleotide mutation in the mouse renin promoter disrupts blood pressure regulation

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