Metabolism and Biological Activities of Angiotensin II and des-Asp1-Angiotensin II in Isolated Adrenal Glomerulosa Cells
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The steroidogenic activities and receptor-binding properties of angiotensin II and des-Asp1-angiotensin II were analyzed and compared with the metabolism of each peptide during incubation with isolated rat and canine adrenal glomerulosa cells. In isolated rat glomerulosa cells, equimolar concentrations of each peptide stimulated aldosterone production similarly over the first 20 min of incubation. However, at later times, the des-Asp1 heptapeptide was consistently less active, with one third the potency of the octapeptide at 40 min, and only one tenth that of the octapeptide after 120 min. In dog glomerulosa cells, the des-Asp1 heptapeptide was less rapidly inactivated and retained one third the potency of the octapeptide after 120 min of incubation. In each species, the maximum aldosterone response to the two peptides was similar at all time intervals studied up to 120 min. Also, no additivity between maximal concentrations of angiotensin II and des-Asp1-angiotensin II was observed. Assay of angiotensin II receptors with radioiodinated and tritiated peptides in rat glomerulosa cells and adrenal particles showed identical receptor concentration for each peptide, with somewhat lower affinity for the heptapeptide (Ka = 0.7 × 109 M-1 for the heptapeptide vs. 2.7 × 109 M-1 for angiotensin II). The metabolism of angiotensin in isolated glomerulosa cells was analyzed by thin layer chromatography and assay of peptides in the incubation medium. Extensive degradation of angiotensin II during incubation with rat cells was detected, with relatively little conversion to the 2–8 and 3–8 peptides. RIA of medium peptides showed decreases to 50% and 30% for angiotensin II and des-Asp1-angiotensin II at 40 min, and to 26% and 10% at 120 min, respectively. Similar results were derived with radioreceptor assay and bioassay by stimulation of aldosterone production in fresh glomerulosa cells. In contrast, metabolism of angiotensin during incubation with dog adrenal glomerulosa cells was less rapid, and both peptides were degraded at the same rate. Analysis of labeled peptides eluted from rat glomerulosa cells after in vivo or in vitro binding of [125I]iodoangiotensin II showed that more than 90% of the bound radioactivity was composed of the octapeptide. These studies have revealed extensive metabolism of angiotensin peptides by isolated rat glomerulosa cells, with more rapid degradation of des-Asp1-angiotensin II than of the native octapeptide. Such peptide metabolism contributes to the apparent discrepancy in biological potencies of angiotensin II and des-Asp1-angiotensin II on aldosterone production in isolated rat glomerulosa cells. It is also evident that angiotensin II acts upon rat and dog glomerulosa cells to evoke aldosterone production without prior conversion to the heptapeptide.Keywords:
Angiotensin III
A novel layer of cells that do not contain both P450aldo and P45011β has been discovered between the zonae glomerulosa and fasciculata of the rat adrenal cortex. Since P450aldo and P45011β are the enzymes responsible for the formation of aldosterone and corticosterone, respectively, the cells in that zone are presumably inert in synthesizing both aldosterone and corticosterone, in other words, the layer is composed of cells that have no zone-specific endocrine function as an adrenocortical component. Cytologically, the layer consists of tightly packed cells, which contain a lesser amount of lipid droplet than the cells in the other zones, and appears as a white ring or a white zone in the double immunostaining with anti P450aldo and and P45011β. Upon angiotensin II-stimulation evoked by Na-deficiency, the number of the zona glomerulosa cells expressing P450aldo increases for the initial 2 or 3 days and then the P450aldo-containing zona glomerulosa cells begin to proliferate. Thus angiotensin II serves as a proliferator of the zona glomerulosa cells of the rat adrenal cortex. During the period, the thickness of the white zone decreases for initial 3 days and becomes constant after 5 or 6 days, being about 5 % of the total cell number of the adrenal cortex.When localization of replicating cells was examined in the adrenal cortex, they were found to be concentrated in and around the white zone. Then the pulse-chase experiments with BrdU showed that the labeled cells migrated out of the white zone and into the zonae fasciculata and rencularis. The localization of the replicating cells in the regenerating adrenal cortex was also around the region between the zonae glomerulosa and fasciculata. On the basis of these findings, we suggest that the newly discovered cell layer (the white zone) is the stem cell zone of the rat adrenal cortex.
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Corticosterone
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Zona fasciculata
Steroid 11-beta-hydroxylase
Corticosterone
Zona reticularis
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3βHSD activity was studied in the adrenal cortex of rats under conditions of sodium restriction, pregnancy or both. The enzyme was shown to be active primarily in the region of the transitional zone and outer fasciculata, indicating that these areas of the adrenal cortex, as well as the zona glomerulosa, are involved when aldosterone production is stimulated. Ultrastructural studies confirmed the histochemical evidence of the involvement of the transitional zone but also provided additional information suggesting a difference in the functional capacities of the zona glomerulosa and the transitional zone. The combined stimuli of sodium restriction and pregnancy led to cellular degradation of the zona glomerulosa (2) but caused no pathological changes in the transitional zone. A suggested role for this zone is that of providing transitional or precursor cells for both the zona glomerulosa and the zona fasciculata. This might account for the fact that its physiological capacity appears to be greater than that of the zona fasciculata.
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Corticosterone
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The adrenal cortex of mammals consists of three concentric zones, i.e., the zona glomerulosa (zG), the zona fasciculata (zF), and the zona reticularis (zR), which secrete mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. In 1994, we identified immunohistochemically a new zone between zG and zF of the rat adrenal gland. The zone appeared to be devoid of any significant endocrine functions specific to adrenocortical zones, therefore, we designated the zone as undifferentiated cell zone (zU). Further, BrdU (5-bromo-2'-deoxyuridine)-incorporating cells (cells in S-phase) were concentrated at the outer region and the inner region of zU, and these cells proliferated and migrated bidirectionally: toward zG centrifugally and toward zF centripetally. We proposed that cells in and around zU are stem/progenitor cells of the rat adrenal cortex, maintaining functional zonation of the adrenal cortex. The view is consistent with observations reported recently that Sonic hedgehog (Shh), an important factor in embryonic development and adult stem cell maintenance, exists in zU of the rat adrenal gland and the Shh-containing cells seem to migrate bidirectionally.
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The adrenal cortex of mammals consists of three concentric zones, i.e., the zona glomerulosa (zG), the zona fasciculata (zF), and the zona reticularis (zR), which secrete mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. In 1994, we identified immunohistochemically a new zone between zG and zF of the rat adrenal gland. The zone appeared to be devoid of any significant endocrine functions specific to adrenocortical zones, therefore, we designated the zone as "undifferentiated cell zone (zU)". Further, BrdU (5-bromo-2′-deoxyuridine)-incorporating cells (cells in S-phase) were concentrated at the outer region and the inner region of zU, and these cells proliferated and migrated bidirectionally: toward zG centrifugally and toward zF centripetally. We proposed that cells in and around zU are stem/progenitor cells of the rat adrenal cortex, maintaining functional zonation of the adrenal cortex. The view is consistent with observations reported recently that Sonic hedgehog (Shh), an important factor in embryonic development and adult stem cell maintenance, exists in zU of the rat adrenal gland and the Shh-containing cells seem to migrate bidirectionally.
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The content of fatty substances was examined: neutral fats, triglycerides and phospholipids, in the adrenal gland cortex after exposing white rats to the influence of detergents in the duration of one month. Neutral fats conduct themselves in the following manner: their quantity is decreased in the cells of zona glomerulosa and is increased in the zona fasciculata and zona reticularis. As far as the presence of triglycerides in the adrenal cortex is concerned, it is typical that they are increased quantity-wise in all three zones of the adrenal gland cortex. Phospholipids in their presence, give the following appearance: this group of fatty substances is of increased content in the cells of zona glomerulosa; a slight increase of these substances is typical for zona fasciculata while their increase is evident in the cells of zona reticularis. All of the described features, regardless of the group of fatty substances, indicate the stimulated activity of the adrenal gland cortex after the application of histochemical methods.
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The aim of the present research is to study the cyclic changes in secretory, destructive and proliferative processes in the adrenal gland cortex of minks. Material and methods . The material is collected between December and April at a monthly interval. The fragments of adrenal glands were fixed in Shtiva, Buen, Zenker fluids and in 10% neutral formalin solutions. PAS-reaction, trichrome-PAS and tetrachrome-PAS staining were applied. RNA was revealed by Brachet’s reaction and by gallocyanine according to Einarson. The material fixed in 10% neutral formalin solution was used to study lipids. Results . Cyclic changes of morphofunctional indices of minks’ adrenal cortex have been studied. In December, zona glomerulosa, zona fasciculate and zona reticularis were clearly manifested. In zona glomerulosa polygonal cells with moderately vacuolated cytoplasm are present. In zona fasciculate there are cells which do not differ from the cells of zona glomerulosa. In January, a decrease in the functional activity of the cortical parenchyma and the development of extensive destructive changes of glandular cells in all zones of the cortical substance of the adrenal cortex were found. In February, extensive proliferative processes and increased secretory activity of the adrenal cortex were observed. Small cells of proliferation centers migrate to zona fasciculate and begin function actively. In March, the recovery processes in the adrenal cortex are finished.
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Parenchyma
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Corticosterone
Steroid 11-beta-hydroxylase
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