The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line

2016 ◽  
Vol 39 (11) ◽  
pp. 758-763 ◽  
Author(s):  
Shin-Ichiro Miura ◽  
Yasunori Suematsu ◽  
Yoshino Matsuo ◽  
Sayo Tomita ◽  
Asuka Nakayama ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Line ◽  
Adrenocortical Cell ◽  
Neprilysin Inhibitor

scholarly journals Glucocorticoid and mineralocorticoid regulation of angiotensin II type 1 receptor binding and inositol triphosphate formation in WB cells

1999 ◽  
Vol 162 (3) ◽  
pp. 381-391 ◽  
Author(s):  
SG Shelat ◽  
LM Flanagan-Cato ◽  
SJ Fluharty
Keyword(s):  
Angiotensin Ii ◽  
Cell Line ◽  
At1 Receptor ◽  
Inositol Triphosphate ◽  
Epithelial Cell Line ◽  
Salt Appetite ◽  
Pressor Responses ◽  
The Brain

Mineralocorticoids, glucocorticoids, and angiotensin II (AngII) act cooperatively to maintain body fluid homeostasis. Mineralocorticoids, such as aldosterone and deoxycorticosterone-acetate (DOCA), function synergistically with AngII in the brain to increase salt appetite and blood pressure. In addition, glucocorticoids increase AngII-induced drinking and pressor responses and may also facilitate the actions of aldosterone on salt appetite. The AngII Type 1 (AT1) receptor mediates many of the physiological and behavioral actions of AngII. This receptor is coupled to the G-protein Gq, which mediates AngII-induced inositol triphosphate (IP3) formation. The WB cell line, a liver epithelial cell line that expresses the AT1 receptor, was used to examine the cellular basis of glucocorticoid and mineralocorticoid regulation of AT1 function. In this study corticosterone and dexamethasone treatments increased the number of AT1 receptors by activating the glucocorticoid receptor (GR). This increase in AT1 binding resulted in enhanced AngII-stimulated IP3 formation. However, only supraphysiological doses of aldosterone or DOCA increased AT1 binding, and this effect also was mediated by GR activation. Furthermore, despite evidence that mineralocorticoids and glucocorticoids function together to increase AngII-stimulated actions in vivo, aldosterone and dexamethasone did not act synergistically to affect AT1 binding, Gq expression, or IP3 formation. These results indicate that GR activation, and the subsequent increases in AT1 binding and in AngII-stimulated IP3 formation, may represent a cellular mechanism underlying the synergy between adrenal steroids and AngII.

scholarly journals Transforming growth factor beta1 inhibits aldosterone and cortisol production in the human adrenocortical cell line NCI-H295R through inhibition of CYP11B1 and CYP11B2 expression

2003 ◽  
Vol 176 (1) ◽  
pp. 69-82 ◽  
Author(s):  
P Liakos ◽  
D Lenz ◽  
R Bernhardt ◽  
JJ Feige ◽  
G Defaye
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Tumor Cell ◽  
Cell Line ◽  
Transforming Growth Factor ◽  
Tumor Cell Line ◽  
Mrna Levels ◽  
Adrenocortical Tumor ◽  
Adrenocortical Cell ◽  
Transforming Growth Factor Beta1

Transforming growth factor beta1 (TGFbeta1) has been shown to exert strong inhibitory effects on adrenocortical cell steroidogenesis. However, the molecular targets of TGFbeta1 in adrenocortical cells appear to differ between species. Here, we report the first characterization of the regulatory effects of TGFbeta1 on the steroidogenic functions of the human adrenocortical tumor cell line NCI-H295R. After treatment with 2 ng/ml TGFbeta1 for 24 h, basal production of corticosterone, cortisol and androstenedione was dramatically decreased. When TGFbeta1 was added simultaneously with forskolin, the production of cortisol and 11-hydroxyandrostenedione was decreased by 85% whereas that of deoxycortisol was increased. When TGFbeta1 was added simultaneously with angiotensin II, aldosterone production was reduced by 80%. We observed that TGFbeta1 strongly inhibits forskolin-induced steroid 11beta-hydroxylase activity and CYP11B1 mRNA levels, as well as angiotensin II-induced aldosterone synthase activity and CYP11B2 mRNA levels. CYP11B1 and CYP11B2 gene products thus appear as the major steroidogenic enzymes down-regulated by TGFbeta1 in the human adrenocortical tumor cell line NCI-H295R.

Effects of Type 1 Insulin-Like Growth Factor Receptor Silencing in a Human Adrenocortical Cell Line

2016 ◽  
Vol 48 (07) ◽  
pp. 484-488 ◽  
Author(s):  
T. Ribeiro ◽  
A. Jorge ◽  
L. Montenegro ◽  
M. Almeida ◽  
B. Ferraz-de-Souza ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Line ◽  
Growth Factor Receptor ◽  
Insulin Like Growth Factor ◽  
Adrenocortical Cell

scholarly journals Angiotensin II type 1 receptor-associated protein deficiency attenuates sirtuin1 expression in an immortalised human renal proximal tubule cell line

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Takahiro Yamaji ◽  
Akio Yamashita ◽  
Hiromichi Wakui ◽  
Kengo Azushima ◽  
Kazushi Uneda ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Proximal Tubule ◽  
Cell Line ◽  
Renal Proximal Tubule ◽  
Sirtuin 1 ◽  
Epithelial Cell Line ◽  
Proximal Tubule Cell ◽  
Deficient Mice

Abstract The proximal tubule is a particularly important site for ageing-related kidney damage. Sirtuin 1 (SIRT1), an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase in the proximal tubule, may be involved in renal injury associated with ageing. However, the mechanisms of SIRT1 regulation remain to be elucidated. We recently reported that angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP)-deficient mice displayed age-associated renal function decline and tubulointerstitial fibrosis. Our data showed that SIRT1 protein expression was reduced in ATRAP-deficient mice, although the relationship between ATRAP deficiency and age-associated renal fibrosis is still not fully understood. It is, therefore, necessary to investigate how ATRAP affects SIRT1 protein expression to resolve ageing-associated kidney dysfunction. Here, since ageing studies are inherently lengthy, we used an ex vivo model of the proximal tubule to determine the role of ATRAP in SIRT1 protein expression. We first generated a clonal immortalised human renal proximal tubule epithelial cell line (ciRPTEC) expressing AT1R and ATRAP. Using this cell line, we demonstrated that ATRAP knockdown reduced SIRT1 protein expression in the ciRPTEC but did not alter SIRT1 mRNA expression. Thus, ATRAP likely mediates SIRT1 protein abundance in ciRPTEC.

scholarly journals Microribonucleic Acid-21 Increases Aldosterone Secretion and Proliferation in H295R Human Adrenocortical Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2477-2483 ◽  
Author(s):  
Damian G. Romero ◽  
Maria W. Plonczynski ◽  
Cristian A. Carvajal ◽  
Elise P. Gomez-Sanchez ◽  
Celso E. Gomez-Sanchez
Keyword(s):  
Cell Proliferation ◽  
Angiotensin Ii ◽  
Cell Line ◽  
Biologically Active ◽  
Cell Physiology ◽  
Adrenocortical Cell ◽  
Aldosterone Secretion ◽  
Adrenocortical Cells ◽  
Expression Levels ◽  
H295r Cells

MicroRNAs (miRNAs) are endogenous small noncoding RNAs that decrease the expression levels of specific genes by translational repression, sequestration, and degradation of their mRNAs. Angiotensin II is an important modulator of adrenal zona glomerulosa cell physiology, including steroidogenesis and proliferation among many other physiological processes. Because each miRNA may regulate the expression levels of multiple genes, thereby resembling the transcription regulatory networks triggered by transcription factors, we hypothesize that specific miRNAs may be involved in angiotensin II-mediated adrenocortical cell physiology. The human adrenocortical cell line H295R is the only adrenal cell line available with a steroid secretion pattern and regulation similar to freshly isolated adrenocortical cells. We screened for miRNAs regulated by angiotensin II in H295R cells and found that miRNA-21 expression levels were specifically modulated by angiotensin II. Angiotensin II time dependently increased miRNA-21 expression reaching a 4.4-fold induction after 24 h. Angiotensin II-mediated miRNA-21 expression resulted in biologically active miRNA-21, determined using a fusion mRNA reporter system carrying miRNA-21 target sequences in its 3′ untranslated region. Up-regulation of miRNA-21 intracellular levels increased aldosterone secretion but not cortisol. Elevation of miRNA-21 levels also increased cell proliferation in H295R cells. In summary, miRNA-21 is an endogenously expressed miRNA in human adrenal cells. miRNA-21 expression is up-regulated by angiotensin II, and its overexpression caused an increase in aldosterone secretion and cell proliferation. Alterations in miRNA-21 expression levels or function may be involved in dysregulation of angiotensin II signaling and abnormal aldosterone secretion by adrenal glands in humans.

scholarly journals Angiotensin II and III Metabolism and Effects on Steroid Production in the HAC15 Human Adrenocortical Cell Line

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 214-221 ◽  
Author(s):  
Kenji Oki ◽  
Phillip G. Kopf ◽  
William B. Campbell ◽  
Milay Luis Lam ◽  
Takeshi Yamazaki ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Line ◽  
Regulatory Protein ◽  
Renin Angiotensin System ◽  
Hydroxysteroid Dehydrogenase ◽  
Zona Glomerulosa ◽  
Cortisol Secretion ◽  
Adrenocortical Cell ◽  
Aldosterone Secretion ◽  
Steroidogenic Acute Regulatory

Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex under primary regulation by the renin-angiotensin system. Angiotensin II (A-II) acts through the angiotensin types 1 and 2 receptors (AT1R and AT2R). A-II is metabolized in different tissues by various enzymes to generate two heptapeptides A-III and angiotensin 1-7, which can then be catabolized into smaller peptides. A-II was more potent than A-III in stimulating aldosterone secretion in the adrenocortical cell line HAC15, and A-II, but not A-III, stimulated cortisol secretion. A-II stimulated mRNA expression of steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase, CYP11B1, and CYP11B2, whereas A-III stimulated 3β-hydroxysteroid dehydrogenase, CYP11B1, and CYP11B2 but decreased the expression of CYP17A1 required for cortisol synthesis. The stimulation of aldosterone secretion by A-II and A-III was blocked by the AT1R receptor blocker, losartan, but not by an AT2R blocker. A-II was rapidly metabolized by the HAC15 cells to mainly to angiotensin 1-7, but not to A-III, and disappeared from the supernatant within 6 h. A-III was metabolized rapidly and disappeared within 1 h. In conclusion, A-II was not converted to A-III in the HAC15 cell and is the more potent stimulator of aldosterone secretion and cortisol of the two. A-III stimulated aldosterone secretion but not cortisol secretion.

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