AT1a Receptor Has Interacted with Angiotensin-converting Enzymes 2 mRNA Expression in Mouse Brainstem
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The CYP11B2 gene encodes aldosterone synthase, a cytochrome P450 (P450aldo) expressed in high levels in the adrenal zona glomerulosa. While the primary physiologic regulators of aldosterone production are circulating angiotensin II (Ang II) and potassium (K+) the action of these agents on CYP11B2 gene transcription have not been examined. Because these factors increase intracellular calcium we have hypothesized that calcium signaling pathways are one mechanism controlling CYP11B2 transcription. Previously we demonstrated that increases in intracellular calcium increase P450aldo mRNA. Herein, we analyzed the role of calcium in the expression of the human CYP11B2 gene using transient transfection of a luciferase reporter construct containing 2017 bp of human CYP11B2 5′ flanking DNA in mouse Y-1 and human H295R adrenocortical cell lines. When transfected into Y-1 cells, reporter gene expression was increased following treatment with ACTH or forskolin, but not with Ang II, the L-type calcium channel agonist BAYK8644, or ionomycin. In H295R cells, however, reporter gene expression was increased following treatment with Ang II, K+, BAYK8644 ionomycin or dibutyryl cAMP (Bu2cAMP). Activation of protein kinase C with TPA did not alter reporter gene expression in either cell line. These data demonstrate that both calcium and cAMP signaling pathways regulate human CYP11B2 gene expression, In addition, the H295R adrenal cell line appears to be an appropriate model to study regulation of CYP 11B2 by calcium.
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Calcium Signaling
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Aim: To observe the effects of different concentrations Angiotensin Ⅱ on the transcription of LOX1 in culture human umbilical vein endothelial cells and to explore its mechanism. Methods: Reverse transcription polymerase chain reaction (RT PCR). Results:①Angiotensin Ⅱ cause a concentration dependent increase of the level of LOX1 mRNA.②Losartan, the inhibitor of AT1 receptor subtypes,inhibited this effects.Conclusion: Angiotensin Ⅱ stimulated the gene expression of LOX1 by activating AT1 receptor subtype in culture human endothelial cells.
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The view that γ-aminobutyric acid (GABA) plays a functional role in non-neuronal tissues, in addition to an inhibitory neurotransmitter role in the mammalian central nervous system, is prevailing, while little attention has been paid to GABAergic signaling machineries expressed by adipocytes to date. In this study, we attempted to demonstrate the possible functional expression of GABAergic signaling machineries by adipocytes.GABA(B) receptor 1 (GABA(B)R1) subunit was constitutively expressed by mouse embryonic fibroblasts differentiated into adipocytes and adipocytic 3T3-L1 cells in culture, as well as mouse white adipose tissue, with no responsiveness to GABA(B)R ligands. However, no prominent expression was seen with mRNA for GABA(B)R2 subunit required for heteromeric orchestration of the functional GABA(B)R by any adipocytic cells and tissues. Leptin mRNA expression was significantly and selectively decreased in adipose tissue and embryonic fibroblasts, along with drastically reduced plasma leptin levels, in GABA(B)R1-null mice than in wild-type mice. Knockdown by siRNA of GABA(B)R1 subunit led to significant decreases in leptin promoter activity and leptin mRNA levels in 3T3-L1 cells.Our results indicate that GABA(B)R1 subunit is constitutively expressed by adipocytes to primarily regulate leptin expression at the transcriptional level through a mechanism not relevant to the function as a partner of heterodimeric assembly to the functional GABA(B)R.
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Aldosterone synthase
Steroid 11-beta-hydroxylase
CAMK
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Short term regulation of aldosterone secretion after stimulation and suppression experiments in mice
Aldosterone is synthesized acutely from the zona glomerulosa cells upon stimulation by the renin-angiotensin-aldosterone system. Several enzymes are involved in this steroidogenic process including the steroidogenic acute regulatory protein (StAR), P450 side chain cleavage enzyme (Cyp11a1), and aldosterone synthase (Cyp11b2) which has been demonstrated to be transcriptionally regulated by the nuclear transcription factors NGF1-B and Nurr1. We investigated the short time transcriptional regulation of these genes in wild-type mice at 10 min intervals for 1 h following application of 0.2 nmol angiotensin II (ANGII) or sodium chloride in comparison sham injections. Using real-time PCR a fast upregulation of adrenal Cyp11b2 expression (53+/-5% increase over baseline) could be observed 10 min after sham injection which was accompanied by a transient increase in aldosterone secretion while StAR and Cyp11a1 upregulation was delayed and more sustained. ANGII caused an increase of StAR and Cyp11a1 expression similar to that observed after sham injection while Cyp11b2 upregulation was more pronounced (10 min, 236+/-39%) and reflected ANGII induced stimulation of aldosterone output. Sodium challenge was followed by a sustained reduction of all three genes examined (Cyp11b2, 20 min, -63+/-6%) which was accompanied by a significant suppression of aldosterone secretion detectable after 60 min. While increases in NGF1-B mRNA levels were similar between the treatment groups, Nurr1 expression levels were induced only upon ANGII administration. These data suggest that acute regulation of aldosterone synthesis is accompanied by fast transcriptional modulation of steroidogenic enzymes and transcription factors that are likely to be involved in aldosterone secretion.
Aldosterone synthase
Steroid 11-beta-hydroxylase
Mineralocorticoid
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Ureteric bud
Mediator
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Endothelin 3
Proenkephalin
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The renin-angiotensin-aldosterone system controls blood pressure and salt-volume homeostasis. Renin, which is the first enzymatic step of the cascade, is critically regulated at the transcriptional level. In the present study, we investigated the role of liver X receptor α (LXRα) and LXRβ in the regulation of renin. In vitro, both LXRs could bind to a noncanonical responsive element in the renin promoter and regulated renin transcription. While LXRα functioned as a cAMP-activated factor, LXRβ was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXRα was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXRα to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXRα–/– mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXRβ–/– mice exhibited reduced kidney renin mRNA levels compared with controls. LXRα–/–LXRβ–/– mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXRα and LXRβ regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXRα signaling pathway is required for the adrenergic control of the renin-angiotensin system.
Liver X receptor
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