Angiotensin II induces coordinated calcium bursts in aldosterone-producing adrenal rosettes

Guagliardo, Nick A.; Klein, Peter; Gancayco, Christina; Lu, Adam C; Leng, Sining; Makarem, Rany R.; Cho, Chelsea; Rusin, Craig G.; Breault, David T.; Barrett, Paula Q.; Beenhakker, Mark P.

doi:10.1038/s41467-020-15408-4

Cited by 23 publications

(21 citation statements)

References 72 publications

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“…Having an extensive epithelial-vascular interface will likely enhance the sensitivity of zG cells to these stimuli and the efficiency of aldosterone release. Interestingly, a recent study by Guagliardo and colleagues revealed zG cells residing within the same rosettes exhibit a highly coordinated Ca 2+ firing activity pattern, showing that the rosette may serve as an organizing center where zG cell response to stimulant can be synchronized and amplified 63 . However, to determine what causes such cooperativity and whether it directly contributes to robust zG function will require extensive future studies.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin and FGFR2 regulate postnatal rosette-based adrenocortical morphogenesis

et al. 2020

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Rosettes are widely used in epithelial morphogenesis during embryonic development and organogenesis. However, their role in postnatal development and adult tissue maintenance remains largely unknown. Here, we show zona glomerulosa cells in the adult adrenal cortex organize into rosettes through adherens junction-mediated constriction, and that rosette formation underlies the maturation of adrenal glomerular structure postnatally. Using genetic mouse models, we show loss of β-catenin results in disrupted adherens junctions, reduced rosette number, and dysmorphic glomeruli, whereas β-catenin stabilization leads to increased adherens junction abundance, more rosettes, and glomerular expansion. Furthermore, we uncover numerous known regulators of epithelial morphogenesis enriched in β-catenin-stabilized adrenals. Among these genes, we show Fgfr2 is required for adrenal rosette formation by regulating adherens junction abundance and aggregation. Together, our data provide an example of rosette-mediated postnatal tissue morphogenesis and a framework for studying the role of rosettes in adult zona glomerulosa tissue maintenance and function.

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Section: Discussionmentioning

confidence: 99%

β-Catenin and FGFR2 regulate postnatal rosette-based adrenocortical morphogenesis

et al. 2020

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“…39 Wide-field microscopy captured calcium-dependent fluorescence signals from individual cells within rosettes. 39 The deletion of TASK-1/-3 from zG cells elicited robust, spontaneous, and periodic (~0.5 Hz) intracellular calcium signals immediately from the onset of the recording period (Figure 1A), in contrast to unstimulated WT zG cells that are largely quiescent until provoked by AngII 39 (Figure S1). To determine the degree of cell activation evoked by zG-TASK-LOF, we plotted fluorescence intensity over time and identified the peak of each oscillatory calcium signal (ie, each calcium spike).…”

Section: Resultsmentioning

confidence: 99%

“…An inter-calcium spike interval histogram revealed 2 populations of calcium spike intervals (Figure S2), as was observed for WT activity. 39 Fitting the histogram to the sum of a Gaussian and an exponential function yielded a threshold value that was used to objectively identify intraburst intervals that segregated three or more individual calcium spikes into distinct bursts. The identification of discrete bursts of calcium spikes enabled the analysis of zG cell burst properties (eg, duration, spike frequency, number).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, these properties in WT slices also remain invariant across various doses of AngII as reported previously. 39 Because AngII-evoked activity increases with time, and spontaneous activity is time invariant, we compared the degree of bursting in both the early (1.5–5.0 minutes) and late phases (5–10 minutes) of the recording period. During the early phase of the recording period, the mean number of spontaneous bursts observed in zG-TASK-LOF slices (14.5±0.4) greatly exceeded that in WT slices evoked by AngIl (7.5±0.3; Figure S3A and S2B).…”

Section: Resultsmentioning

confidence: 99%

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Intrinsic Adrenal TWIK-Related Acid-Sensitive TASK Channel Dysfunction Produces Spontaneous Calcium Oscillations Sufficient to Drive AngII (Angiotensin II)-Unresponsive Hyperaldosteronism

et al. 2022

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BACKGROUND: Ion channel mutations in calcium regulating genes strongly associate with AngII (angiotensin II)-independent aldosterone production. Here, we used an established mouse model of in vivo aldosterone autonomy, Cyp11b2 -driven deletion of TWIK-related acid-sensitive potassium channels (TASK-1 and TASK-3, termed zona glomerulosa [zG]-TASK-loss-of-function), and selective pharmacological TASK channel inhibition to determine whether channel dysfunction in native, electrically excitable zG cell rosette-assemblies: (1) produces spontaneous calcium oscillatory activity and (2) is sufficient to drive substantial aldosterone autonomy. METHODS: We imaged calcium activity in adrenal slices expressing a zG-specific calcium reporter (GCaMP3), an in vitro experimental approach that preserves the native rosette assembly and removes potentially confounding extra-adrenal contributions. In parallel experiments, we measured acute aldosterone production from adrenal slice cultures. RESULTS: Absent from untreated WT slices, we find that either adrenal-specific genetic deletion or acute pharmacological TASK channel inhibition produces spontaneous oscillatory bursting behavior and steroidogenic activity (2.4-fold) that are robust, sustained, and equivalent to activities evoked by 3 nM AngII in WT slices. Moreover, spontaneous activity in zG-TASK-loss-of-function slices and inhibitor-evoked activity in WT slices are unresponsive to AngII regulation over a wide range of concentrations (50 pM to 3 µM). CONCLUSIONS: We provide proof of principle that spontaneous activity of zG cells within classic rosette assemblies evoked solely by a change in an intrinsic, dominant resting-state conductance can be a significant source of AngII-independent aldosterone production from native tissue.

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“…Aldosterone biosynthesis is under the control of potassium and angiotensin II, which increase the levels of CYP 11B2 mRNA and lead to an increase in the activity of aldosterone synthase [ 54 , 55 , 56 , 57 , 58 ]. High potassium diets in rats increase the expression of CYP11B2 in the adrenal gland and aldosterone production [ 59 ].…”

Section: Contribution Of Dna Methylation To Human Cyp11b2 Transcriptionmentioning

confidence: 99%

DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

Takeda

Demura

Yoneda

et al. 2021

IJMS

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Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene CYP11B2 is regulated by angiotensin II and potassium. DNA methylation negatively regulates AGT and CYP11B2 expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the CYP11B2 promoter region, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac AGT expression. CpG dinucleotides in the CYP11B2 promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated CYP11B2 promoter. Low salt intake and angiotensin II infusion lead to upregulation of CYP11B2 expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases CYP11B2 expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased CYP11B2 expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both AGT and CYP11B2 contribute to the pathogenesis of cardiovascular diseases.

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Angiotensin II induces coordinated calcium bursts in aldosterone-producing adrenal rosettes

Cited by 23 publications

References 72 publications

β-Catenin and FGFR2 regulate postnatal rosette-based adrenocortical morphogenesis

β-Catenin and FGFR2 regulate postnatal rosette-based adrenocortical morphogenesis

Intrinsic Adrenal TWIK-Related Acid-Sensitive TASK Channel Dysfunction Produces Spontaneous Calcium Oscillations Sufficient to Drive AngII (Angiotensin II)-Unresponsive Hyperaldosteronism

DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

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