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Cell Death & Disease Mar 2020Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate...
Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an iron-dependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC values of 5.7 × 10, 8.1 × 10 and 2.1 × 10 M, respectively, while all non-steroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.
Topics: Adrenal Cortex; Adrenal Gland Diseases; Cell Death; Ferroptosis; Gonadal Steroid Hormones; Humans
PubMed: 32184394
DOI: 10.1038/s41419-020-2385-4 -
Veterinary Pathology Mar 2009Neoplastic adrenocortical lesions are common in humans and several species of domestic animals. Although there are unanswered questions about the origin and evolution of... (Review)
Review
Neoplastic adrenocortical lesions are common in humans and several species of domestic animals. Although there are unanswered questions about the origin and evolution of adrenocortical neoplasms, analysis of human tumor specimens and animal models indicates that adrenocortical tumorigenesis involves both genetic and epigenetic alterations. Chromosomal changes accumulate during tumor progression, and aberrant telomere function is one of the key mechanisms underlying chromosome instability during this process. Epigenetic changes serve to expand the size of the uncommitted adrenal progenitor population, modulate their phenotypic plasticity (i.e., responsiveness to extracellular signals), and increase the likelihood of subsequent genetic alterations. Analyses of heritable and spontaneous types of human adrenocortical tumors documented alterations in either cell surface receptors or their downstream effectors that impact neoplastic transformation. Many of the mutations associated with benign human adrenocortical tumors result in dysregulated cyclic adenosine monophosphate signaling, whereas key factors and/or signaling pathways associated with adrenocortical carcinomas include dysregulated expression of the IGF2 gene cluster, activation of the Wnt/beta-catenin pathway, and inactivation of the p53 tumor suppressor. A better understanding of the factors and signaling pathways involved in adrenal tumorigenesis is necessary to develop targeted pharmacologic and genetic therapies.
Topics: Adrenal Cortex; Adrenal Cortex Neoplasms; Animals; Cattle; Cricetinae; Ferrets; Goats; Humans; Mice
PubMed: 19261630
DOI: 10.1354/vp.46-2-194 -
Molecular and Cellular Endocrinology Apr 2011The origins of our understanding of the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification... (Review)
Review
The origins of our understanding of the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland have arisen from studies on the role of Sf1 in steroidogenesis and adrenal development initiated 20 years ago in the laboratory of Dr. Keith Parker. Adrenocortical stem/progenitor cells have been predicted to be undifferentiated and quiescent cells that remain at the periphery of the cortex until needed to replenish the organ, at which time they undergo proliferation and terminal differentiation. Identification of these stem/progenitor cells has only recently been explored. Recent efforts have examined signaling molecules, including Wnt, Shh, and Dax1, which may coordinate intricate lineage and signaling relationships between the adrenal capsule (stem cell niche) and underlying cortex (progenitor cell pool) to maintain organ homeostasis in the adrenal gland.
Topics: Adrenal Cortex; Animals; Cell Differentiation; Cell Lineage; Humans; Models, Biological; Organogenesis; Stem Cells
PubMed: 21094677
DOI: 10.1016/j.mce.2010.11.012 -
Physiological Reviews Apr 1957
Topics: Adrenal Cortex; Epinephrine; Humans; Sympathetic Nervous System
PubMed: 13441422
DOI: 10.1152/physrev.1957.37.2.155 -
Endocrinology Feb 2018The atrophy and hypofunction of the adrenal cortex following long-term pharmacologic glucocorticoid therapy is a major health problem necessitating chronic...
The atrophy and hypofunction of the adrenal cortex following long-term pharmacologic glucocorticoid therapy is a major health problem necessitating chronic glucocorticoid replacement that often prolongs the ultimate return of endogenous adrenocortical function. Underlying this functional recovery is anatomic regeneration, the cellular and molecular mechanisms of which are poorly understood. Investigating the lineage contribution of cortical Sonic hedgehog (Shh)+ progenitor cells and the SHH-responsive capsular Gli1+ cells to the regenerating adrenal cortex, we observed a spatially and temporally bimodal contribution of both cell types to adrenocortical regeneration following cessation of glucocorticoid treatment. First, an early repopulation of the cortex is defined by a marked delamination and expansion of capsular Gli1+ cells, recapitulating the establishment of the capsular-cortical homeostatic niche during embryonic development. This rapid repopulation is promptly cleared from the cortical compartment only to be supplanted by repopulating cortical cells derived from the resident long-term-retained zona glomerulosa Shh+ progenitors. Pharmacologic and genetic dissection of SHH signaling further defines an SHH-dependent activation of WNT signaling that supports regeneration of the cortex following long-term glucocorticoid therapy. We define the signaling and lineage relationships that underlie the regeneration process.
Topics: Adrenal Cortex; Adrenal Glands; Animals; Female; Glucocorticoids; Hedgehog Proteins; Male; Mice; Mice, Inbred C57BL; Regeneration; Signal Transduction; Stem Cells; Wnt4 Protein; Zinc Finger Protein GLI1; Zona Glomerulosa
PubMed: 29211850
DOI: 10.1210/en.2017-03061 -
Journal of Feline Medicine and Surgery Jun 2020A notable, although relatively uncommon, finding during feline ovariohysterectomy is the presence of parovarian nodules, located proximal to the ovary, near or within...
OBJECTIVES
A notable, although relatively uncommon, finding during feline ovariohysterectomy is the presence of parovarian nodules, located proximal to the ovary, near or within the ovarian vascular bundle. They are usually 2-3 mm in diameter, white-to-tan in color and glandular in appearance. The objective of this study was to either decisively reinforce the existing findings reported in the literature, which suggest that these parovarian nodules are incidental adrenocortical nodules that are clinically and surgically insignificant, or capture any samples that were not ectopic adrenal tissue in order to characterize them histologically.
METHODS
Ninety-one formalin-preserved tissue sections containing parovarian nodules were collected during routine feline elective ovariohysterectomy and evaluated histologically.
RESULTS
Definitive histologic information was obtained from 73/91 (80.2%) submitted samples. Fifty-two of 73 (71.2%) samples were determined to contain accessory adrenal gland cortex. Twenty of 73 (27.4%) samples were determined to contain residual mesonephric structures. While accessory adrenocortical nodules were found bilaterally in cats of all ages, mesonephric structures were predominantly right-sided, and only found in one cat over the age of 1 year. Ectopic or accessory ovarian tissue was not found in any of the samples.
CONCLUSIONS AND RELEVANCE
This study adds to the existing body of data which suggest these nodules are incidental structures that do not need to be removed during surgical sterilization. However, further in vivo studies with larger sample sizes and years of follow-up would be required to more definitively prove this theory.
Topics: Adrenal Cortex; Animals; Cats; Female; Hysterectomy; Ovary
PubMed: 31411532
DOI: 10.1177/1098612X19867166 -
Hypertension (Dallas, Tex. : 1979) Dec 2020Primary aldosteronism is a frequent form of endocrine hypertension caused by aldosterone overproduction from the adrenal cortex. Regulation of aldosterone biosynthesis...
Primary aldosteronism is a frequent form of endocrine hypertension caused by aldosterone overproduction from the adrenal cortex. Regulation of aldosterone biosynthesis has been studied in rodents despite differences in adrenal physiology with humans. We, therefore, investigated pig adrenal steroidogenesis, morphology, and transcriptome profiles of the zona glomerulosa (zG) and zona fasciculata in response to activation of the renin-angiotensin-aldosterone system by dietary sodium restriction. Six-week-old pigs were fed a low- or high-sodium diet for 14 days (3 pigs per group, 0.4 g sodium/kg feed versus 6.8 g sodium/kg). Plasma aldosterone concentrations displayed a 43-fold increase (=0.011) after 14 days of sodium restriction (day 14 versus day 0). Low dietary sodium caused a 2-fold increase in thickness of the zG (<0.001) and an almost 3-fold upregulation of (<0.05) compared with high dietary sodium. Strong immunostaining of the KCNJ5 (G protein-activated inward rectifier potassium channel 4), which is frequently mutated in primary aldosteronism, was demonstrated in the zG. mRNA sequencing transcriptome analysis identified significantly altered expression of genes modulated by the renin-angiotensin-aldosterone system in the zG (n=1172) and zona fasciculata (n=280). These genes included many with a known role in the regulation of aldosterone synthesis and adrenal function. The most highly enriched biological pathways in the zG were related to cholesterol biosynthesis, steroid metabolism, cell cycle, and potassium channels. This study provides mechanistic insights into the physiology and pathophysiology of aldosterone production in a species closely related to humans and shows the suitability of pigs as a translational animal model for human adrenal steroidogenesis.
Topics: Adrenal Cortex; Aldosterone; Animals; Cytochrome P-450 CYP1B1; Diet, Sodium-Restricted; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Humans; Male; Renin-Angiotensin System; Sodium, Dietary; Steroids; Swine; Transcriptome; Zona Fasciculata; Zona Glomerulosa
PubMed: 33070662
DOI: 10.1161/HYPERTENSIONAHA.120.15998 -
Pharmacological Reports : PR 2012This study was performed to investigate expression and distribution of glucocorticoid receptor (GR) in the rat adrenal cortex, acute effect of ethanol on its expression...
BACKGROUND
This study was performed to investigate expression and distribution of glucocorticoid receptor (GR) in the rat adrenal cortex, acute effect of ethanol on its expression and possible role of endogenous nitric oxide (NO) in this phenomenon.
METHODS
Adult female Wistar rats showing diestrus day 1 were treated with: a) ethanol (2 or 4 g/kg body weight (b.w.), ip), b) N(ω)-nitro-L-arginine methyl ester (L-NAME), well-known competitive inhibitor of all isoforms of NO synthase (NOS), (30 mg/kg b.w., sc) followed by ethanol (4 g/kg, ip) 3 h later and c) L-NAME (30 mg/kg b.w., sc) followed by saline (ip) 3 h later. Untreated rats were used as controls. Adrenocortical expression of GR was estimated by immunohistochemistry.
RESULTS
Strong nuclear GR staining was observed throughout the cortex of control rats. Acute ethanol treatment significantly decreased the expression of GR in the zona fasciculata and zona reticularis. Blockade of NO formation had no influence on this effect of ethanol, whereas L-NAME itself induced significant decline in GR immunoreactivity.
CONCLUSIONS
Obtained findings are the first to demonstrate localization and distribution of the GR throughout the rat adrenal cortex and to suggest that ethanol as well as endogenous NO may modulate adrenocortical expression of this steroid receptor.
Topics: Adrenal Cortex; Animals; Ethanol; Female; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Receptors, Glucocorticoid
PubMed: 23087141
DOI: 10.1016/s1734-1140(12)70884-8 -
Molecular and Cellular Endocrinology Feb 2007The existence and location of undifferentiated cells with the capability of maintaining the homeostasis of the adrenal cortex have long been sought. These cells are... (Review)
Review
The existence and location of undifferentiated cells with the capability of maintaining the homeostasis of the adrenal cortex have long been sought. These cells are thought to remain mostly quiescent with a potential to commit to self-renewal processes or terminal differentiation to homeostatically repopulate the organ. In addition, in response to physiologic stress, the undifferentiated cells undergo rapid proliferation to accommodate organismic need. Sufficient adrenocortical proliferative capacity lasting the lifespan of the host has been demonstrated through cell transplantation and enucleation experiments. Labeling experiments with tritium, BrdU, or trypan blue, as well as transgenic assays support the clonogenic identity and location of these undefined cells within the gland periphery. We define undifferentiated adrenocortical cells as cells devoid of steroidogenic gene expression, and differentiated cells as cells with steroidogenic capacity. In this review, we discuss historic developmental studies together with recent molecular examinations that aim to characterize such populations of cells.
Topics: Adrenal Cortex; Animals; Cell Differentiation; Humans; Stem Cells
PubMed: 17240045
DOI: 10.1016/j.mce.2006.12.028 -
Scientific Reports Jan 2020Adrenal cortex autotransplantation with ACTH stimulation may be an alternative therapy for patients with bilateral adrenalectomy to avoid adrenal crisis, but its...
Adrenal cortex autotransplantation with ACTH stimulation may be an alternative therapy for patients with bilateral adrenalectomy to avoid adrenal crisis, but its underlying mechanism has not been elucidated. Previously, we detected Dhh upregulation in rat adrenocortical autografts after transplantation. Here, we investigated potential regulators such as Gata4, Gata6, Sry and Sox9 which affect Dhh transcription in adrenocortical autografts with or without ACTH stimulation. In ACTH-stimulated autografts, Gata4 and Gata6 were downregulated compared to control autografts. This response was linked to rDhh repression. A reporter assay using the upstream region of rDhh and a GATA binding motif revealed that rDhh promoters were significantly upregulated by co-transfection with Gata4 or Gata6 or both. Sry and Sox9 expression in autografts with or without ACTH stimulation were verified by PCR and RNAscope analyses. The ovarian differentiation factors Foxl2 and Rspo1 were also upregulated in the autografts. Gata4 and Gata6 were found to be significant factors in the regulation of rDhh expression and could be associated with adrenocortical autograft maintenance. Gonadal primordia with bipotential testicular and ovarian functions may also be present in these autografts.
Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Animals; GATA4 Transcription Factor; GATA6 Transcription Factor; Hedgehog Proteins; Rats; Regeneration; Transplantation, Autologous; Up-Regulation
PubMed: 31949236
DOI: 10.1038/s41598-019-57351-5