Adrenal cortex development and related disorders leading to adrenal insufficiency.

The adult human adrenal cortex produces steroid hormones that are crucial for life, supporting immune response, glucose homeostasis, salt balance and sexual maturation. It consists of three histologically distinct and functionally specialized zones. The fetal adrenal forms from mesodermal material and produces predominantly adrenal C19 steroids from its fetal zone, which involutes after birth. Transition to the adult cortex occurs immediately after birth for the formation of the zona glomerulosa and fasciculata for aldosterone and cortisol production and continues through infancy until the zona reticularis for adrenal androgen production is formed with adrenarche. The development of this indispensable organ is complex and not fully understood. This article gives an overview of recent knowledge gained of adrenal biology from two perspectives: one, from basic science studying adrenal development, zonation and homeostasis; and two, from adrenal disorders identified in persons manifesting with various isolated or syndromic forms of primary adrenal insufficiency.

ß-Catenin and FGFR2 regulate postnatal rosette-based adrenocortical morphogenesis.

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 ß-catenin results in disrupted adherens junctions, reduced rosette number, and dysmorphic glomeruli, whereas ß-catenin stabilization leads to increased adherens junction abundance, more rosettes, and glomerular expansion. Furthermore, we uncover numerous known regulators of epithelial morphogenesis enriched in ß-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.

Regulation of Proliferative Processes in Rat Adrenal Cortex by Transcriptional Factor PRH under Conditions of Developmental Exposure to Endocrine Disruptor DDT.

The effects of endocrine disrupters of transcriptional control of morphogenesis are poorly studied. Changes in the expression of transcriptional factor PRH and proliferation of adrenal cortical cells were analyzed in pubertal and postpubertal rats exposed prenatally and postnatally to low doses of endocrine disrupter DDT. In rats exposed to DDT, the expression of PRH and proliferation of adrenal cortical cells differed from those in control rats. Association between these parameters was weakened in the zona glomerulosa and zona reticularis and was absent in the zona fasciculata. These findings suggest that exposure to DDT in pre- and postnatal periods impairs the regulation of proliferative processes by transcriptional factor PRH in all zones of rat adrenal cortex, which can be a mechanism of the disruptive action of DDT.

Changes in Canonical ß-Catenin/Wnt Signaling Activation in the Adrenal Cortex of Rats Exposed to Endocrine Disruptor Dichlorodiphenyltrichloroethane (DDT) during Prenatal and Postnatal Ontogeny.

Prenatal and postnatal exposure to low doses of the endocrine disruptor dichlorodiphenyltrichloroethane (DDT) leads to delayed activation of the canonical ß-catenin/Wnt signaling in zona glomerulosa and zona reticularis of the adrenal cortex in rats, which changed the rate of their postnatal development. Suppression of the Wnt pathway in zona fasciculata promotes its regeneration after DDT-induced blood circulation disorders and cell death.

Development of adrenal cortex zonation.

The human adult adrenal cortex is composed of the zona glomerulosa (zG), zona fasciculata (zF), and zona reticularis (zR), which are responsible for production of mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. The final completion of cortical zonation in humans does not occur until puberty with the establishment of the zR and its production of adrenal androgens; a process called adrenarche. The maintenance of the adrenal cortex involves the centripetal displacement and differentiation of peripheral Sonic hedgehog-positive progenitors cells into zG cells that later transition to zF cells and subsequently zR cells.

Development of adrenal cortical zonation and expression of key elements of adrenal androgen production in the chimpanzee (Pan troglodytes) from birth to adulthood.

The basis for the pattern of adrenal androgen production in the chimpanzee, which resembles that of humans, is poorly defined. We characterized the developmental zonation and expression of elements of the androgen biosynthetic pathway in the chimpanzee adrenal. The newborn adrenal contained a broad fetal zone (FZ) expressing CYP17, SULT2A1, and Cytochrome B5 (CB5) but not HSD3B; the outer cortex expressed HSD3B but not SULT2A1 or CB5. During infancy, the FZ involuted and the HSD3B-expressing outer cortex broadened. By 3years of age, a thin layer of cells that expressed CB5, SULT2A1, and CYP17 adjoined the medulla and likely represented the zona reticularis; the outer cortex consisted of distinct zonae fasiculata and glomerulosa. Thereafter, the zona reticularis broadened as also occurs in the human. The adult chimpanzee adrenal displayed other human-like characteristics: intramedullary clusters of reticularis-like cells and also a cortical cuff of zona fasiculata-like cells adjoining the central vein.

Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells.

Lineage conversion of differentiated cells in response to hormonal feedback has yet to be described. To investigate this, we studied the adrenal cortex, which is composed of functionally distinct concentric layers that develop postnatally, the outer zona glomerulosa (zG) and the inner zona fasciculata (zF). These layers have separate functions, are continuously renewed in response to physiological demands, and are regulated by discrete hormonal feedback loops. Their cellular origin, lineage relationship, and renewal mechanism, however, remain poorly understood. Cell-fate mapping and gene-deletion studies using zG-specific Cre expression demonstrate that differentiated zG cells undergo lineage conversion into zF cells. In addition, zG maintenance is dependent on the master transcriptional regulator Steroidogenic Factor 1 (SF-1), and zG-specific Sf-1 deletion prevents lineage conversion. These findings demonstrate that adrenocortical zonation and regeneration result from lineage conversion and may provide a paradigm for homeostatic cellular renewal in other tissues.

Sonic hedgehog signaling during adrenal development.

It has been speculated for a number of years that Sonic hedgehog (Shh) signaling plays an important role in adrenal development. Over the past two years several reports have described the expression and function of Shh pathway genes in the adrenal cortex, using primarily mouse models. The key findings are that Shh signals produced by a population of partially differentiated cortical cells located in the outer cortex/zona glomerulosa are received by non-cortical mesenchymal cells located predominantly in the overlying capsule. This signal is required for growth of both the capsule and the cortex, but not for cortical zonation or steroidogenic cell differentiation. Using molecular genetic tools to define the adrenocortical cell lineages that are descended from both Shh signaling and receiving cells, both capsule and cortical cells were found to have properties of adrenocortical stem and/or progenitor cells. Here we place these observations within the context of prior studies on adrenal development, postnatal adrenal maintenance and adrenocortical stem/progenitor cell lineages.

Effects of intrauterine malnutrition on the renal morphology of Wistar rats: a systematic review

Introduction: Many epidemiological studies suggest that the intrauterine environment is extremely importantto the determination of the individual’s future health. Alterations in the maternal nutritional state, reflectedon the weight on birth, may program the litter for the development of diseases on the adult age. Studies withanimals exposed to intrauterine malnutrition have suggested a reduction in the number of glomeruli, as wellas arterial pressure increase. To review in the literature the alterations of the renal physiology of adult Wistarrats exposed to malnourishment during intrauterine life. Material and methods: A search was performedin the following databases: SciELO, MEDLINE, PUBMED, SCIENCE DIRECT and LILACS. The mainsearch terms were “malnutrition” and “renal function” both in Portuguese and in English. Were includedoriginal articles involving albino rats. Were excluded the review articles as well as those involving humanbeings. Results: According to Franco et al. (2009) the renal function and the number of glomeruli werereduced by the intrauterine malnutrition, predisposing the adult animals to renal diseases. For Chen and Chou(2009) the glomerular ultrastructure is not affected by maternal undernutrition, suggesting that this factordoes not contribute to the hypertension pathogenesis after maternal malnutrition. Conclusion: Intrauterinemalnourishment seems to interfere in the renal functions programming with alterations to the glomerulimorphology, but its mechanisms are yet uncertain. More randomized studies and clinical essays are suggestedin order to comprehend the factors that cause such process.

Zone-specific cell proliferation during compensatory adrenal growth in rats.

Compensatory adrenal growth after unilateral adrenalectomy (ULA) leads to adrenocortical hyperplasia. Because zonal growth contributions are not clear, we characterized the phenotype of cortical cells that proliferate using immunofluorescence histochemistry and zone-specific cell counting. Rats underwent ULA, sham adrenalectomy (sham), or no surgery and were killed at 2 or 5 days. Adrenals were weighed and sections immunostained for Ki67 (proliferation), cytochrome P-450 aldosterone synthase (P450aldo, glomerulosa), and cytochrome P-450 11beta-hydroxylase (P45011beta, fasciculata). Unbiased stereology was used to count proliferating glomerulosa and fasciculata cells. Adrenal weight increased after ULA compared with sham and no surgery at both time points, and there was no difference between sham and no surgery. However, either ULA or sham increased Ki67-positive cells in the outer fasciculata at both time points compared with no surgery. Outer fasciculata-restricted proliferation is thus associated with adrenal weight gain in ULA but not sham. Experiment repetition using proliferating cell nuclear antigen and bromodeoxyuridine showed similar results. After ULA, adrenal DNA, RNA, and protein increased at both time points, whereas after sham, only adrenal DNA increased at 2 days. Compensatory growth thus results from hyperplasia and hypertrophy, whereas sham induces only a transient adrenal hyperplasia. Dexamethasone pretreatment prevented the increase in adrenal weight after ULA and blocked Ki67 labeling in the outer fasciculata but not zona glomerulosa in all groups. These results clearly show that the outer fasciculata is the primary adrenal zone responsible for compensatory growth, responding to steroid-suppressible stress signals that alone are ineffective in increasing adrenal mass.