Increased Renin Production in Mice With Deletion of Peroxisome Proliferator-Activated Receptor-γ in Juxtaglomerular Cells

Desch, Michael; Schreiber, Andrea; Schweda, Frank; Madsen, Kirsten; Friis, Ulla Glenert; Weatherford, Eric T.; Sigmund, Curt D.; López, María Luisa S. Sequeira; Gómez, R. Ariel; Todorov, Vladimir

doi:10.1161/hypertensionaha.109.138800

Cited by 23 publications

(20 citation statements)

References 32 publications

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“…Previous three-dimensional reconstruction studies by our group demonstrated that the afferent arterioles of practically all glomeruli (> 98%) in the adult mouse kidney are renin-positive [25]. Therefore, the number of reninpositive glomeruli per slide statistically reflects the number of renin-expressing cells and thus the expression rate of renin protein in the single afferent arteriole [5].…”

Section: Reninmentioning

confidence: 79%

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

Desch

Harlander

Neubauer

et al. 2011

Pflugers Arch - Eur J Physiol

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This study aimed to assess the role of cAMP target sequences enhancer cAMP response element (enhCRE) and cAMP and overlapping negative response element (CNRE) in the control of human renin gene (REN) in vivo. enhCRE and CNRE were silenced by mutations in a 12.2-kb human renin promoter fused to LacZ reporter gene. This construct was used to generate transgenic mice (RENMut-LacZ). The expression of the transgene was correctly targeted to the juxtaglomerular portions of renal afferent arterioles which express endogenous mouse renin. Therefore, enhCRE and CNRE do not seem to be relevant for the control of the cell-specific expression of the human renin gene. The β-adrenoreceptor agonist isoproterenol (10 mg/kg/day, for 2 days) stimulated the endogenous renin, but not the LacZ mRNA expression. Treatment of RENMut-LacZ mice with the angiotensin converting enzyme inhibitor (enalapril 10 mg/kg/day, for 7 days) or their crossing to angiotensin receptor type 1a knockout mice led to increased renin and LacZ mRNA levels. Renin expression was upregulated by low-salt diet (0.03% NaCl, for 10 days) and downregulated by high-salt diet (4% NaCl, for 10 days). In contrast, low-salt diet did not influence, while high-salt diet inhibited the expression of LacZ. In summary, enhCRE and CNRE appear to be necessary for the transactivation of the human renin gene through β-adrenoreceptors and by low-salt diet. Our data also suggest that different intracellular mechanisms mediate the effect of low- and high-salt intake on renin expression in vivo.

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Section: Reninmentioning

confidence: 79%

“…The number of renin/LacZ-positive glomeruli is directly proportional to the number of renin/LacZ-positive cells in the afferent arterioles (see also "Discussion") [5].…”

Section: Three-dimensional Reconstructionmentioning

confidence: 97%

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

Desch

Harlander

Neubauer

et al. 2011

Pflugers Arch - Eur J Physiol

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“…The latter model has been widely used for the conditional inactivation of different genes expressed in the renin-secreting granular cells of the juxtaglomerular apparatus in the kidney. [21][22][23][24][25][26][27][28][29] These studies showed that, at the whole-organ level, the Ren1 d Cre is strongly expressed in the kidney, whereas in other tested tissues, the Cre expression was at or near background levels. 24 Nota bene, clearly, however, these results did not exclude that there might be minor populations of Cre-expressing cells in other tissues as well.…”

Section: Discussionmentioning

confidence: 99%

“…[21][22][23][24][25][26][27][28][29] These studies showed that, at the whole-organ level, the Ren1 d Cre is strongly expressed in the kidney, whereas in other tested tissues, the Cre expression was at or near background levels. 24 Nota bene, clearly, however, these results did not exclude that there might be minor populations of Cre-expressing cells in other tissues as well. These studies also showed that, within the kidney, the Cre expression is not limited to the granular cells but also present in the rest of the afferent arterioles, the Circadian Clocks in the Kidney interlobular renal arteries, and the tubular segments.…”

Section: Discussionmentioning

confidence: 99%

Local Renal Circadian Clocks Control Fluid–Electrolyte Homeostasis and BP

Tokonami¹,

Mordasini²,

Pradervand

et al. 2014

Journal of the American Society of Nephrology

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107

101

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The circadian timing system is critically involved in the maintenance of fluid and electrolyte balance and BP control. However, the role of peripheral circadian clocks in these homeostatic mechanisms remains unknown. We addressed this question in a mouse model carrying a conditional allele of the circadian clock gene Bmal1 and expressing Cre recombinase under the endogenous Renin promoter (Bmal1 Cre mice exhibited multiple abnormalities, including increased urine volume, changes in the circadian rhythm of urinary sodium excretion, increased GFR, and significantly reduced plasma aldosterone levels. These changes were accompanied by a reduction in BP. These results show that local renal circadian clocks control body fluid and BP homeostasis. Circadian rhythmicity is a feature of a wide variety of physiologic functions. Many of the functional rhythms are driven by the circadian timing system, a complex mechanism that coordinates all major cellular processes with geophysical time. It is thought that this coordination allows for the anticipatory adaptation of cells and tissues to the circadian changes in functional requirements. The circadian timing system is organized in a hierarchical manner. The master clock of the system is located in the suprachiasmatic nucleus of the hypothalamus and synchronized to the daily light/dark cycle through the retinohypothalamic tract. The peripheral circadian clocks, which are present in virtually all peripheral tissues, are synchronized to geophysical time through a wide range of master clock-dependent stimuli, many of which remain unknown (reviewed in ref. 1 ). It is important to note, however, that, despite the hierarchical structure of the circadian timing system and its continuous resetting by environmental time cues, the intrinsic activity of both central and peripheral circadian clocks is largely self-sustained. On the molecular level, the master clock and peripheral clocks share similar machinery based on transcriptional/translational feedback loops involving transcriptional activators BMAL1, CLOCK, and NPAS2 and their own repressors PER1 and PER2 as well as CRY1 and CRY2 (reviewed in ref. 2 ).The circadian timing system is critically involved in the maintenance of fluid and electrolyte balance

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“…The third site is of particular interest because it is part of a TGACCT direct repeat that makes up a larger HRE which partially accounts for the increased enhancer activity observed in the mouse (15). The HRE can bind the retinoic acid receptor (RAR), retinoid X receptor (RXR), Nr2f6 (EAR2), peroxisome proliferator-activated receptor (PPAR␥), and vitamin D receptor (VDR) (8,22,23,31). However, VDR has been reported to exert its effects indirectly by binding CREB and inhibiting its transactivation through the CRE (38).…”

mentioning

confidence: 99%

Regulation of renin expression by the orphan nuclear receptors Nr2f2 and Nr2f6

Weatherford

Liu

2012

American Journal of Physiology-Renal Physiology

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Understanding the transcriptional mechanisms of renin expression is key to understanding the regulation of the renin-angiotensin system. We previously identified the nuclear receptors RAR/RXR and Nr2f6 (EAR2) as positive and negative transcriptional regulators of renin expression, respectively (Liu X, Huang X, Sigmund CD. Circ Res 92: 1033-1040, 2003). Both mediate their effects through a hormone response element (HRE) within the renin enhancer. Here, we determined whether another nuclear receptor, Nr2f2 (Coup-TFII, Arp-1), identified in a screen of proteins that bind the HRE, also regulates renin expression. Luciferase assays indicate that Nr2f2 negatively regulates the renin promoter more potently than Nr2f6. Gel-shift and chromatin immunoprecipitation (ChIP) indicate that Nr2f2 and Nr2f6 can bind directly to the renin enhancer through the HRE. Surprisingly, baseline expression of endogenous renin was not effected when Nr2f2 was knocked down in As4.1 cells, whereas knockdown of Nr2f6 increased renin expression twofold. Interestingly, however, knockdown of Nr2f2 augmented the induction of renin expression caused by retinoic acid. These data indicate that both Nr2f6 and Nr2f2 can negatively regulate the renin promoter, under baseline conditions and in response to physiological queues, respectively. Therefore, Nr2f2 may require an initiating signal that results in a change at the chromatin level or activation of another transcription factor to exert its effects. We conclude that both Nr2f2 and Nr2f6 negatively regulate renin promoter activity, but may do so by divergent mechanisms.

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Increased Renin Production in Mice With Deletion of Peroxisome Proliferator-Activated Receptor-γ in Juxtaglomerular Cells

Cited by 23 publications

References 32 publications

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

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

Local Renal Circadian Clocks Control Fluid–Electrolyte Homeostasis and BP

Regulation of renin expression by the orphan nuclear receptors Nr2f2 and Nr2f6

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