cis-regulatory elements and trans-acting factors directing basal and cAMP-stimulated human renin gene expression in chorionic cells.

In the kidney, renin gene expression is exquisitely localized to the juxtaglomerular (JG) cells lining the afferent arteriole, having the capacity to regulate renin synthesis in response to a variety of physiological cues. We investigated human renin gene expression in transgenic mice containing a genomic construct driven by 149 bp of its proximal promoter to elucidate whether this was sufficient to confer JG-specific expression. Whereas human renin mRNA was permissively expressed in most tissues, the transgene was expressed mainly in JG cells in the kidney. Active human renin and human prorenin were found in the systemic circulation at levels consistent with previous transgenic models. Remarkably, two lines displayed an appropriate upregulation of transgene mRNA in response to angiotensin-converting enzyme inhibition, and two lines exhibited a downregulation of transgene mRNA in response to subpressor and pressor doses of ANG II. Our results suggest that 149 bp of the human renin proximal promoter, in a context of a genomic construct, are sufficient to confer human renin expression in renal JG cells and at least some aspects of appropriate regulation.

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HUMAN RENIN GENE EXPRESSION DURING PREGNANCY IN TRANSGENIC MICE. † 367

Pediatric Research ◽

10.1203/00006450-199604001-00387 ◽

1996 ◽

Vol 39 ◽

pp. 64-64

Author(s):

David C Merrill ◽

Shane Smith ◽

Bruno Granwehr ◽

Cayla Carney ◽

Curt Sigmund

Keyword(s):

Gene Expression ◽

Transgenic Mice ◽

Human Renin ◽

Renin Gene

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Transcriptional and posttranscriptional mechanisms regulate human renin gene expression in Calu-6 cells

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.1.f94 ◽

1996 ◽

Vol 271 (1) ◽

pp. F94-F100 ◽

Cited By ~ 6

Author(s):

J. A. Lang ◽

L. H. Ying ◽

B. J. Morris ◽

C. D. Sigmund

Keyword(s):

Transcriptional Activity ◽

De Novo ◽

Gene Transfection ◽

Fold Increase ◽

Regulatory Elements ◽

Human Renin ◽

Renin Gene ◽

A Cell ◽

Silencer Element ◽

Basal Transcriptional Activity

We have recently identified a human pulmonary carcinoma cell line (Calu-6) that expresses human renin (hREN) mRNA endogenously, and we use it herein as a model to examine the regulation of the hREN gene. Transfection analysis of a deletion series (-2750 to -149) of hREN promoter-luciferase fusion constructs revealed the presence of multiple weak regulatory elements within the first 1,301 bp of the 5'-flanking region and a classic silencer element within the first intron (intron A) of the gene. The 5'-flanking regulatory domain consisted of three closely linked elements, two negative and one positive, each contributing a cell-specific threefold modulation of transcriptional activity. Treating Calu-6 cells with forskolin caused a 100-fold increase in steady-state endogenous hREN mRNA but no increase in hREN promoter activity in transient transfections or in nuclear runoff transcription assays. Nevertheless, de novo transcription and translation were necessary for adenosine 3',5'-cyclic monophosphate (cAMP)-mediated induction. Our results suggest that multiple regulatory elements regulate basal transcriptional activity of the hREN gene and the increase in hREN mRNA by cAMP may be mediated by posttranscriptional mechanisms.

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The Pal3 Promoter Sequence Is Critical for the Regulation of Human Renin Gene Transcription by Peroxisome Proliferator-Activated Receptor-γ

Endocrinology ◽

10.1210/en.2008-0127 ◽

2008 ◽

Vol 149 (9) ◽

pp. 4647-4657 ◽

Cited By ~ 20

Author(s):

Vladimir T. Todorov ◽

Michael Desch ◽

Thomas Schubert ◽

Armin Kurtz

Keyword(s):

Gene Expression ◽

Gene Transcription ◽

Promoter Activity ◽

Peroxisome Proliferator ◽

Response Element ◽

Peroxisome Proliferator Activated Receptor ◽

Human Renin ◽

Pparγ Agonist ◽

Renin Gene ◽

Stimulation Of

We recently reported that human renin gene transcription is stimulated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ in the renin-producing cell line Calu-6. The effect of PPARγ was mapped to two sequences in the renin promoter: a direct repeat hormone response element (HRE), which is related to the classical PPAR response element (PPRE) and a nonconsensus palindromic element with a 3-bp spacer (Pal3). We now find that PPARγ binds to the renin HRE. Neither the human renin HRE nor the consensus PPRE was sufficient to attain the maximal stimulation of renin promoter activity by the PPARγ agonist rosiglitazone. In contrast, the human renin Pal3 element mediates both the full PPARγ-dependent activation of transcription and the PPARγ-driven basal renin gene transcription. The human renin Pal3 sequence was found to selectively bind PPARγ and the retinoid X receptor-α from Calu-6 nuclear extracts. This is in contrast to the consensus PPRE, which can bind other nuclear proteins. PPARγ knockdown paradoxically did not attenuate the stimulation of the endogenous renin gene expression by rosiglitazone. Similarly, a deficiency of PPARγ did not attenuate the activation of the minimal human renin promoter, which contains the endogenous Pal3 motif. However, when the human renin Pal3 site was replaced by the consensus PPRE sequence, PPARγ knockdown abrogated the effect of rosiglitazone on renin promoter activity. Thus, the human renin Pal3 site appears to be critical for the PPARγ-dependent regulation of gene expression by mediating maximal transcription activation, particularly at the low cellular level of PPARγ.

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cAMP target sequences enhCRE and CNRE sense low-salt intake to increase human renin gene expression in vivo

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-011-0956-z ◽

2011 ◽

Vol 461 (5) ◽

pp. 567-577 ◽

Cited By ~ 12

Author(s):

Michael Desch ◽

Sabine Harlander ◽

Björn Neubauer ◽

Melanie Gerl ◽

Stephane Germain ◽

...

Keyword(s):

Gene Expression ◽

Salt Intake ◽

Human Renin ◽

Low Salt ◽

Renin Gene ◽

Target Sequences

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Pressure-natriuresis and -diuresis in transgenic rats harboring both human renin and human angiotensinogen genes.

Journal of the American Society of Nephrology ◽

10.1681/asn.v9122212 ◽

1998 ◽

Vol 9 (12) ◽

pp. 2212-2222

Author(s):

B Dehmel ◽

E Mervaala ◽

A Lippoldt ◽

V Gross ◽

J Bohlender ◽

...

Keyword(s):

Gene Expression ◽

Renin Angiotensin System ◽

Renal Perfusion ◽

Transgenic Rat ◽

Water Excretion ◽

Excretory Function ◽

Human Renin ◽

Renin Gene ◽

Renin Mrna ◽

Pressure Natriuresis

The hypertensive double transgenic rat harboring both the human renin and human angiotensinogen genes (dTGR) offers a unique opportunity to study the human renin-angiotensin system in an experimental animal model. Since nothing is known about the control of sodium and water excretion in these rats, this study was performed to compare pressure-natriuresis relationships in hypertensive dTGR and normotensive control rats harboring only the human renin gene (hREN), in order to determine how the pressure-natriuresis relationship is reset in hypertensive dTGR. To differentiate between extrinsic and intrinsic renal mechanisms, experiments were performed with and without renal denervation, and with and without infusions of vasopressin, norepinephrine, 17-OH-corticosterone, and aldosterone. Human and rat angiotensinogen and renin mRNA expression were also determined. In hREN without controlled renal function, urine flow and sodium excretion increased from 13 to 169 microl/min per g kidney wet weight (kwt) and from 1 to 30 micromol/min per g kwt, respectively, as renal perfusion pressure was increased from 67 to 135 mmHg. Renal blood flow (RBF) and GFR ranged between 3 to 7 and 0.9 to 1.5 ml/min per g kwt. In dTGR, pressure-natriuresis-diuresis relationships were shifted approximately 40 mmHg rightward. RBF was lower in dTGR than in hREN; GFR was not different. In dTGR with neurohormonal factors controlled, RBF was decreased and pressure-natriuresis-diuresis curves were not different compared to dTGR curves without these interventions. By light microscopy, the kidneys of these 6-wk-old dTGR and hREN rats were normal and indistinguishable. Both human and rat renin and angiotensinogen mRNA were expressed in the kidneys of dTGR. The two renin mRNA were decreased in dTGR, indicating a physiologic downregulation of renin gene expression by high BP. It is concluded that the renal pressure-natriuresis mechanism is reset toward higher pressure levels in dTGR and participates in the maintenance of hypertension. The reduced excretory function in dTGR depends on hREN and human angiotensinogen gene expression and is intrinsic to the kidney as opposed to extrarenal regulators.

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