Changes of the CYP11B2 Expressing Zona Glomerulosa in Human Adrenals From Birth to 40 Years of Age

Abstract

Background: Aldosterone synthase (CYP11B2) antibodies for immunohistochemistry, enables to visualize aldosterone-producing zona glomerulosa (ZG), aldosterone-producing micronodules, and aldosterone-producing adenomas. The architecture of the ZG differs in old versus young age but the evolution of the changes is not well known. The pathogenesis of aldosterone-producing micronodules and aldosterone-producing adenomas is still unclear and research on the ZG in young populations is limited. In this study, we elucidate changes in human ZG with age by quantifying the CYP11B2 expression. Methods: We collected 83 human adrenal glands from 57 autopsy cases aged 0 to 40 years old. In 26 cases, both adrenals were available. We performed immunohistochemistry targeting CYP11B2 and quantified the relative CYP11B2 expressing area, CYP11B2 continuity, the mean gap length between CYP11B2-expressing areas and the maximum extension of CYP11B2 area (depth). Results: We found a negative correlation between age and the relative CYP11B2 expressing area, a negative correlation between age and CYP11B2 continuity, a positive correlation between age and mean gap length, and a positive correlation between age and maximum CYP11B2 depth. The changes in expression patterns of relative CYP11B2 expressing area, CYP11B2 continuity and mean gap length were seen in both adrenals of the same autopsy case. Conclusions: The decline of relative CYP11B2 expressing ZG area and continuity may indicate involution of the ZG, which is supported by an increase of gaps and maximum CYP11B2 depth indicating clustering, comparable to formation of aldosterone-producing micronodules. The similarities in both adrenals from the same case indicate that these changes occur bilaterally.

Ectopic localization of CYP11B1 and CYP11B2-expressing cells in the normal human adrenal gland

“…The mechanism involved in the maintenance of the differentiated cortex probably follows different ways in these species by activating specific signaling pathways besides those targeted by trophic factors such as angiotensin II and potassium for the ZG cells and ACTH for the ZF cells. Our data together with previously published results [11,12,26,27], suggest that the model of functional zonation defined in rats and mice (two animal models used as surrogates for the human adrenal cortex) may not be extrapolated to humans and appears therefore inconclusive regarding the maintenance of zonal differentiation of the human cortex. In fact, while the functional ZG does correspond to the H-E defined zonation for individuals between birth and 11 years of age [11,12,26,27], the adrenal cortex then rapidly undergoes profound functional remodeling during life span.…”

“…Our data together with previously published results [11,12,26,27], suggest that the model of functional zonation defined in rats and mice (two animal models used as surrogates for the human adrenal cortex) may not be extrapolated to humans and appears therefore inconclusive regarding the maintenance of zonal differentiation of the human cortex. In fact, while the functional ZG does correspond to the H-E defined zonation for individuals between birth and 11 years of age [11,12,26,27], the adrenal cortex then rapidly undergoes profound functional remodeling during life span. This process likely results from various causes such as the high sodium/lowpotassium diet which induces a suppression of the renin-angiotensin-aldosterone system and subsequently a lack of stimulation of the ZG [11,12,26,27].…”

“…In fact, while the functional ZG does correspond to the H-E defined zonation for individuals between birth and 11 years of age [11,12,26,27], the adrenal cortex then rapidly undergoes profound functional remodeling during life span. This process likely results from various causes such as the high sodium/lowpotassium diet which induces a suppression of the renin-angiotensin-aldosterone system and subsequently a lack of stimulation of the ZG [11,12,26,27]. As a consequence, the cells expressing CYP11B2 progressively begin to decline in the subcapsular region and are replaced by neighboring CYP11B1-expressing cells probably under the influence of the extracellular matrix (ECM) scaffold which contains binding domains and releases chemoattractant molecules [34].…”

“…With the use of these antibodies it appeared that the normal adult human adrenal cortex zonation was more complex than in rodents. The expression of CYP11B2 was mostly continuous in adrenal glands derived from young individuals, whereas its expression became discontinuous and sparse in adrenal glands older subjects [10][11][12], with the exception of rare clusters of CYP11B2 expressing cells, called aldosterone-producing cell clusters (APCCs). These APCCs have initially been defined as groups of morphological ZG cells close to the capsule and inner ZF-like cells isolated from the neighboring CYP11B1 expressing cells by a defined border [6,11].…”

Molecular and Epigenetic Control of Aldosterone Synthase, CYP11B2 and 11-Hydroxylase, CYP11B1

“…The adrenal cortex is composed of three functional zones. The zona glomerulosa, the outer zone of the gland, expresses aldosterone synthase, CYP11B2, which catalyzes the synthesis of aldosterone [ 13 ]. The renin-angiotensin system (RAS) and potassium regulate CYP11B2 expression.…”