The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and hyperaldosteronism
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE102963 | GEO | 2018/05/01
REPOSITORIES: GEO
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Project description:The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and hyperaldosteronism
| PRJNA399641 | ENA
Project description:Primary aldosteronism (PA) is a common form of endocrine hypertension suspected in the presence of arterial hypertension (HT), hypokalemia and low plasma renin levels. While for a long time the genetic causes of PA have remained mysterious, recent findings have revealed an important role for an altered function of potassium channels in the pathogenesis of this disease. The basis for the unique sensitivity of adrenal zona glomerulosa (ZG) cells for plasma potassium concentration is a very high background potassium conductance, which is dependent on expression at high levels of two 2-pore domain (K2P) potassium channels, Task1 (KCNK3) and Task3 (KCNK9. Recent studies have shown that mice lacking Kcnk3 (Task1) or both Kcnk3 and Kcnk9 have PA. In Kcnk3 null mice, hyperaldosteronism is present in young animals of either sex, but is corrected in males after puberty. Strikingly, in these animals hyperaldosteronism associates with abnormal adrenal cortex functional zonation, since Cyp11b2, the rate-limiting enzyme for aldosterone production, is expressed in the inner region of the adrenal cortex and not in the glomerulosa. Additionally, this phenotype is under the control of sex hormones, as shown by the fact that castration of male Kcnk3 -/- animals prevents normal Cyp11b2 distribution, while testosterone injection in female Kcnk3 null mice restores expression of Cyp11b2 in ZG cells. We took advantage of the unique characteristics of the Kcnk3 null mouse model to search for genes that can modify their phenotype of PA and adrenocortical functional zonation. Using gene expression profiling in the adrenal glands of Kcnk3 null mice and exploiting the possibility of modulation of their phenotype by sexual hormones, we identified a cluster of genes closely associated with hyperaldosteronism in a sex- and hormone-dependent dynamic fashion. Among these genes, we focused our attention on Dkk3 (dickkopf3), encoding a peculiar member of the dickkopf family of Wnt signalling modulators because of its close association with aldosterone-producing cells in humans (11). Inactivation of Dkk3 in the Kcnk3 null background causes extension of the hyperaldosteronemic phenotype and increased expression of Cyp11b2 in the adrenal gland to the male sex, without affecting functional zonation. These data indicate that Dkk3 is a component of the genetic circuitry regulating expression of Cyp11b2 and suggest that it may be implicated in the pathogenesis of low-renin hyperaldosteronism in humans. One color -experiment with 2 strains of mice: C57BL/6 WT or Kcnk3 null (KO): male and female in basal conditions or following hormonal treatment (castration for males and testosterone injection for females), corresponding to 8 groups of animals. Total of 24 samples (n=3).
2012-08-20 | E-GEOD-37825 | biostudies-arrayexpress
Project description:Primary aldosteronism (PA) is a common form of endocrine hypertension suspected in the presence of arterial hypertension (HT), hypokalemia and low plasma renin levels. While for a long time the genetic causes of PA have remained mysterious, recent findings have revealed an important role for an altered function of potassium channels in the pathogenesis of this disease. The basis for the unique sensitivity of adrenal zona glomerulosa (ZG) cells for plasma potassium concentration is a very high background potassium conductance, which is dependent on expression at high levels of two 2-pore domain (K2P) potassium channels, Task1 (KCNK3) and Task3 (KCNK9. Recent studies have shown that mice lacking Kcnk3 (Task1) or both Kcnk3 and Kcnk9 have PA. In Kcnk3 null mice, hyperaldosteronism is present in young animals of either sex, but is corrected in males after puberty. Strikingly, in these animals hyperaldosteronism associates with abnormal adrenal cortex functional zonation, since Cyp11b2, the rate-limiting enzyme for aldosterone production, is expressed in the inner region of the adrenal cortex and not in the glomerulosa. Additionally, this phenotype is under the control of sex hormones, as shown by the fact that castration of male Kcnk3 -/- animals prevents normal Cyp11b2 distribution, while testosterone injection in female Kcnk3 null mice restores expression of Cyp11b2 in ZG cells. We took advantage of the unique characteristics of the Kcnk3 null mouse model to search for genes that can modify their phenotype of PA and adrenocortical functional zonation. Using gene expression profiling in the adrenal glands of Kcnk3 null mice and exploiting the possibility of modulation of their phenotype by sexual hormones, we identified a cluster of genes closely associated with hyperaldosteronism in a sex- and hormone-dependent dynamic fashion. Among these genes, we focused our attention on Dkk3 (dickkopf3), encoding a peculiar member of the dickkopf family of Wnt signalling modulators because of its close association with aldosterone-producing cells in humans (11). Inactivation of Dkk3 in the Kcnk3 null background causes extension of the hyperaldosteronemic phenotype and increased expression of Cyp11b2 in the adrenal gland to the male sex, without affecting functional zonation. These data indicate that Dkk3 is a component of the genetic circuitry regulating expression of Cyp11b2 and suggest that it may be implicated in the pathogenesis of low-renin hyperaldosteronism in humans.
2012-08-20 | GSE37825 | GEO
Project description:Primary aldosteronism (PA), a common cause of severe hypertension, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) and 80 additional probands with unsolved early-onset PA. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of the identical p.Arg172Gln mutation; all relatives with early-onset PA carried the CLCN2 variant found in probands. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. In this data set, we examined RNA expression in H295R cells transfected with empty vector, WT and p.Arg172Gln CLCN2. Expression of CLCN2 led to increased expression of CYP11B2 and its upstream regulator NR4A2.
2017-12-08 | GSE107030 | GEO
Project description:Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. Inactivation of Rarα in mice led to major structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA.
2019-10-21 | GSE136801 | GEO
Project description:Primary aldosteronism (PA), the most common form of endocrine hypertension, is characterized by inappropriately elevated aldosterone production via renin-independent mechanisms. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2)-guided sequencing approach. Herein, using CYP11B2-guided whole-exome sequencing (WES) and targeted amplicon sequencing, we detected two closely-stationed somatic variants in SLC30A1 in five APAs (p.L51_A57del, n=3; p.L49_L55del, n=2) that were devoid of any of the known aldosterone-driver mutations. SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). PA cases with SLC30A1 mutations showed male dominance and demonstrated increased serum aldosterone concentration compared with age-matched male controls. We tested functional effects of the variant SLC30A1L51_A57del in a doxycycline-inducible system using the human adrenocortical HAC15 cell line. Functional in vitro studies following doxycycline treatment indicated increased adrenal cell aldosterone production, CYP11B2 mRNA expression, CYP11B2 promoter activity, depolarization of the resting membrane potential and increased cytosolic Ca2+ levels in the SLC30A1L51_A57del cells. Collectively, these data support a pathological role for mutant SLC30A1 on the development of PA.
2023-07-03 | GSE236437 | GEO
Project description:The mineralocorticoid aldosterone mainly produced by the adrenal gland is essential for life but an abnormal excessive secretion causes severe pathological effects including hypertension and target organ injury in the heart and kidney. The aim of this study was to determine the gene regulatory network triggered by aldosterone secretagogues in a non transformed cell system. Freshly isolated rat adrenal zona glomerulosa cells were stimulated with the two main aldosterone secretagogues, angiotensin II and potassium, for two hours and subjected to whole genome expression studies using multiple biological and bioinformatics tools. Several genes were differentially expressed by Ang II (n=133) or potassium (n=216). Genes belonging to the nucleic acid binding and transcription factor activity categories were significantly enriched. A subset of the most regulated genes were confirmed by real-time RT-PCR and then their expression analyzed in time curve studies. Differentially expressed genes were grouped according to their time-response expression pattern and their promoter regions analyzed for common regulatory transcription factors binding sites. Finally, data mining with gene promoters, transcription factors and literature databases were performed to generate gene interaction networks for either Ang II or potassium. This study provides for the first time a complete study of the genes that are regulated, and the interaction between them, by aldosterone secretagogues in rat adrenal cells. Increasing our knowledge of adrenal physiology and gene regulation in non transformed cell systems would lead us to a better approach for discovery of candidate genes involved pathological conditions of the adrenal cortex. Experiment Overall Design: Freshly isolated rat adrenal cells were treated with Ang II (100 nM) or potassium (16 mM) for 2 h at 37C. Experiment Overall Design: Total RNA from three independent experiments were isolated, labeled and hybridized to whole genome high-density oligonucleotide microarrays (Affymetrix Rat Genome 230 2.0). Experiment Overall Design: 3 independent cell preparations. Experiment Overall Design: In each experiement there is one tube control, one Ang II (100 nM) and potassium (16 mM).
2008-10-18 | E-GEOD-8421 | biostudies-arrayexpress
Project description:The adrenal cortex is characterized by a distinct architecture as well as a high density of specialized sinusoidal blood vessels. The preservation of this particular endothelial cell phenotype is likely vital for proper adrenal gland function. The aldosterone-producing zona glomerulosa harbors macrophages in close association with sinusoidal capillaries. However, the function of this macrophage-endothelial cell-juxtaposition in steady-state conditions is unknown. We show that macrophages preserve capillary specialization in the adrenal gland and modulate aldosterone secretion. By combining macrophage-specific deletion of the angiogenic cytokine Vascular Endothelial Growth Factor A (VEGF-A), single-cell transcriptomics and functional phenotyping, we provide evidence that loss of VEGF-A in myeloid cells, including adrenal gland macrophages depletes a specialized subset of PLVAP+ fenestrated endothelial cells in the zona glomerulosa of mice, along with increased deposition of basement membrane collagen IV and in
2024-06-24 | GSE245128 | GEO
Project description:The mineralocorticoid aldosterone mainly produced by the adrenal gland is essential for life but an abnormal excessive secretion causes severe pathological effects including hypertension and target organ injury in the heart and kidney. The aim of this study was to determine the gene regulatory network triggered by aldosterone secretagogues in a non transformed cell system. Freshly isolated rat adrenal zona glomerulosa cells were stimulated with the two main aldosterone secretagogues, angiotensin II and potassium, for two hours and subjected to whole genome expression studies using multiple biological and bioinformatics tools. Several genes were differentially expressed by Ang II (n=133) or potassium (n=216). Genes belonging to the nucleic acid binding and transcription factor activity categories were significantly enriched. A subset of the most regulated genes were confirmed by real-time RT-PCR and then their expression analyzed in time curve studies. Differentially expressed genes were grouped according to their time-response expression pattern and their promoter regions analyzed for common regulatory transcription factors binding sites. Finally, data mining with gene promoters, transcription factors and literature databases were performed to generate gene interaction networks for either Ang II or potassium. This study provides for the first time a complete study of the genes that are regulated, and the interaction between them, by aldosterone secretagogues in rat adrenal cells. Increasing our knowledge of adrenal physiology and gene regulation in non transformed cell systems would lead us to a better approach for discovery of candidate genes involved pathological conditions of the adrenal cortex. Keywords: agent response
2008-06-29 | GSE8421 | GEO
Project description:The adrenal cortex is characterized by a distinct architecture as well as a high density of specialized sinusoidal blood vessels. The preservation of this particular endothelial cell phenotype is likely vital for proper adrenal gland function. The aldosterone-producing zona glomerulosa harbors macrophages in close association with sinusoidal capillaries. However, the function of this macrophage-endothelial cell-juxtaposition in steady-state conditions is unknown. We show that macrophages preserve capillary specialization in the adrenal gland and modulate aldosterone secretion. By combining macrophage-specific deletion of the angiogenic cytokine Vascular Endothelial Growth Factor A (VEGF-A), single-cell transcriptomics and functional phenotyping, we provide evidence that loss of VEGF-A in myeloid cells, including adrenal gland macrophages depletes a specialized subset of PLVAP+ fenestrated endothelial cells in the zona glomerulosa of mice, along with increased deposition of basement membrane collagen IV and induction of sub-endothelial fibrosis.
2024-06-24 | GSE245127 | GEO