Endothelium-Derived Steroidogenic Factor Enhances Angiotensin II-Stimulated Aldosterone Release by Bovine Zona Glomerulosa Cells

Hanke, Craig J.; Holmes, Blythe B.; Xu, Yafei; Nithipatikom, Kasem; Campbell, William B.

doi:10.1210/en.2006-0884

Cited by 7 publications

(7 citation statements)

References 43 publications

(65 reference statements)

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“…18,19 Alternatively, Ang IV and Ang (1-7) did not stimulate aldosterone production in bovine adrenal zona glomerulosa cells. 16 Because the primary Ang II metabolite from the cortical arteries was Ang (1-7), we predict that vascular Ang II metabolism would reduce Ang II stimulation of steroid hormone release.…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin II Relaxations of Bovine Adrenal Cortical Arteries

et al. 2008

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Abstract-Angiotensin (Ang) II regulates adrenal steroidogenesis and adrenal cortical arterial tone. Vascular metabolism could decrease Ang II concentrations and produce metabolites with vascular activity. Our goals were to study adrenal artery Ang II metabolism and to characterize metabolite vascular activity. Bovine adrenal cortical arteries were incubated with Ang II (100 nmol/L) for 10 and 30 minutes. Metabolites were analyzed by mass spectrometry. Ang (1-7), Ang III, and Ang IV concentrations were 146Ϯ21, 173Ϯ42 and 58Ϯ11 pg/mg at 10 minutes and 845Ϯ163, 70Ϯ14, and 31Ϯ3 pg/mg at 30 minutes, respectively. Concentration-related relaxations of U46619-preconstricted cortical arteries to Ang II (maximum relaxationϭ29Ϯ3%; EC 50 ϭ3.4 pmol/L) were eliminated by endothelium removal and inhibited by the NO synthase inhibitor, nitro-L-arginine (30 mol/L; maximum relaxationϭ14Ϯ7%). Ang II relaxations were enhanced by the angiotensin type-1 receptor antagonist losartan (1 mol/L; maximum relaxationϭ41Ϯ3%; EC 50 ϭ11 pmol/L). Losartan-enhanced Ang II relaxations were inhibited by nitro-L-arginine (maximum relaxationϭ18Ϯ5%) and the angiotensin type-2 receptor antagonist PD123319 (10 mol/L; maximum relaxationϭ27Ϯ5%). Ang (1-7) and Ang III caused concentration-related relaxations with less potency (EC 50 ϭ43 and 24 nmol/L, respectively) but similar efficacy (maximum relaxationsϭ39Ϯ3% and 48Ϯ5%, respectively) as losartan-enhanced Ang II relaxations. Ang (1-7) relaxations were inhibited by nitro-L-arginine (maximum relaxationϭ16Ϯ4%) and the Ang (1-7) receptor antagonist 7 D -Ala-Ang (1-7) (1 mol/L; maximum relaxationϭ10Ϯ3%) and eliminated by endothelium removal. Thus, Ang II metabolism by adrenal cortical arteries to metabolites with decreased vascular activity represents an inactivation pathway possibly decreasing Ang II presentation to adrenal steroidogenic cells and limits Ang II vascular effects.

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Section: Discussionmentioning

confidence: 99%

“…16,17 Although Ang III is equipotent to Ang II in stimulating steroidogenesis, 18,19 Ang IV and Ang (1-7) are inactive. 16 Ang II metabolism by intact adrenal arteries has not been evaluated, and, thus, the consequence of this metabolism on adrenal arterial vascular tone has not been characterized.…”

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Angiotensin II Relaxations of Bovine Adrenal Cortical Arteries

et al. 2008

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“…173,209 ALDO also increases vascular endothelial stiffness, leading to endothelial dysfunction, which favors proteinuria. 210–214 According to recent studies, the adverse effect of AT II appears to be dependent on the contribution from ALDO. 215–217…”

Section: Cardiac and Renal Abnormalities Related To Ras Overactivitymentioning

confidence: 99%

Intracardiac and Intrarenal Renin-Angiotensin Systems: Mechanisms of Cardiovascular and Renal Effects

Raizada

Skipper

Luo

et al. 2007

Journal of Investigative Medicine

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The renin-angiotensin system (RAS) is a hormonal system that controls body fluid volume, blood pressure, and cardiovascular function in both health and disease. Various tissues, including the heart and kidneys, possess individual locally regulated RASs. In each RAS, the substrate protein angiotensinogen is cleaved by the peptidases renin and angiotensin-converting enzyme to form the biologically active product angiotensin II, which acts as an intracrine cardiac and renal hormone. The components of each RAS, including aldosterone (ALDO), may be produced locally and/or may be delivered by or sequestered from the circulation. Overactivity of the cardiac RAS has been associated with cardiac diseases, including cardiac hypertrophy due to volume and/or pressure overload, heart failure, coronary artery disease with myocardial infarction, and hypertension. Overactivity of the renal RAS has been associated with various kidney diseases, including nephropathies and renal artery stenosis. The principal effects of an overactive RAS include the generation of reactive oxygen species, which leads to "oxidative stress," activation of the nuclear transcription factor kappaB, and stimulation of pathways and genes that promote vasoconstriction, endothelial dysfunction, cell hypertrophy, fibroblast proliferation, inflammation, excess extracellular matrix deposition, atherosclerosis, and thrombosis. It has been suggested that oxidative stress is the central mechanism underlying the pathogenesis of RAS-related and ALDO-related chronic cardiovascular and renal tissue injury and of cardiac arrhythmias and conduction disturbances.

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“…The study also includes in-vitro experiments to assess formation of Ang 1-7 by ACE2 on adrenal cells. Previous studies have shown that small amounts of Ang 1-7 can be synthesized from Ang II, in adrenocortical cells [5,6] but the contribution of ACE2 to this process is unknown. Experiments by Caroccia et al suggest that local ACE2 does not contribute significantly to the synthesis of Ang 1-7 in adrenal tissues as basal Ang 1-7 production, in an adrenal adenocarcinoma cell line (NCI-H295), is not affected by an ACE2 inhibitor.…”

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Angiotensin-converting enzyme type 2 and aldosterone synthesis: beyond the renin--angiotensin--aldosterone system and closer to the clinic

Pena‐Silva

Heistad

2021

Journal of Hypertension

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A n important part of the renin-angiotensin-aldosterone system (RAAS) is the angiotensin-converting enzyme type 2 (ACE2), angiotensin (Ang) 1-7, Mas receptor axis (Fig. 1). ACE2, a homologue of ACE expressed in multiple tissues, removes the last amino acid from peptides, such as Ang I or II to form Ang 1-9 or Ang 1-7, respectively [1]. Despite its structural similarity to Ang II, Ang 1-7 acts mainly through the Mas receptor. In general, Ang 1-7/ACE2 modulate effects of Ang II, especially in blood vessels, as Ang II produces vasoconstriction and induces oxidative stress and inflammation, whereas Ang 1-7 produces vasodilatation and attenuates oxidative stress, inflammation, fibrosis and vascular remodeling [2,3]. In contrast to effects of Ang 1-7/ACE2 on blood vessels, little is known about their effects on the adrenal gland, and in fact, effects on the adrenal gland in humans are not known at all. In this issue of the Journal of Hypertension, Caroccia et al. [4] examine effects of ACE2 and Ang 1-7 on aldosterone synthesis by the adrenal gland, thus filling an important gap in our knowledge.To explore effects of ACE2 and Ang 1-7 on aldosterone synthesis, Caroccia et al. studied specimens obtained at surgery, and plasma samples, from patients with aldosterone-producing adenomas (APA). The authors also used an adrenocortical adrenome cell line and tissue-protein extracts, to evaluate effects on Ang II-stimulated aldosterone synthesis of ACE2, activators and inhibitors of ACE2 and Ang 1-7. Their results demonstrate that ACE2 is expressed at measurable levels in the adrenal cortex, and its expression is reduced by about half in samples of aldosterone-producing adenomas. Despite expression of ACE2 in adrenal glands, no detectable levels of Ang 1-7 were found in tissues, or in plasma draining from adrenal veins from APA or contralateral glands. These results suggest that there is not a clinically relevant production of Ang 1-7 in adrenal glands (Fig. 1).The study also includes in-vitro experiments to assess formation of Ang 1-7 by ACE2 on adrenal cells. Previous studies have shown that small amounts of Ang 1-7 can be synthesized from Ang II, in adrenocortical cells [5,6] but the contribution of ACE2 to this process is unknown. Experiments by Caroccia et al. suggest that local ACE2 does not contribute significantly to the synthesis of Ang 1-7 in adrenal tissues as basal Ang 1-7 production, in an adrenal adenocarcinoma cell line (NCI-H295), is not affected by an ACE2 inhibitor. Nevertheless, formation of Ang 1-7 increased, almost 100-fold, when tissue extracts were spiked with recombinant human ACE2. The authors confirmed that a widely used experimental drug, DIZE, does not act as an ACE2 activator, although in low doses, it increased ACE2 expression, by a yet unknown mechanism.Finally, the authors examined effects of Ang 1-7 on aldosterone and cortisol synthesis. Aldosterone synthase (CYP11B2) and 11 Beta hydroxylase (CYP11B1) are key enzymes for production of aldosterone and cortisol. The enzymes are expressed in the a...

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Endothelium-Derived Steroidogenic Factor Enhances Angiotensin II-Stimulated Aldosterone Release by Bovine Zona Glomerulosa Cells

Abstract: Endothelium-derived steroidogenic factor (EDSF) is an endo-

Cited by 7 publications

References 43 publications

Angiotensin II Relaxations of Bovine Adrenal Cortical Arteries

Angiotensin II Relaxations of Bovine Adrenal Cortical Arteries

Intracardiac and Intrarenal Renin-Angiotensin Systems: Mechanisms of Cardiovascular and Renal Effects

Angiotensin-converting enzyme type 2 and aldosterone synthesis: beyond the renin--angiotensin--aldosterone system and closer to the clinic

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