Proliferation of Capsular Stem Cells Induced by Acth in the Rat Adrenal Cortex

Abstract

Despite great efforts devoted to clarifying the localization of proliferative activity in the adrenal cortex, the agents that stimulate proliferation remain controversial, and the nature of the stem cells from which cortical cells differentiate is incompletely understood. We studied proliferative activity in the rat adrenal cortex using an immunohistochemical method to detect the presence of the Proliferating Cell Nuclear Antigen (PCNA) (an intranuclear enzyme whose synthesis reaches the maximum intensity during the S-phase of the cell cycle). Groups of six rats were subjected to daily intraperitoneal injection of either corticotropin (ACTH1-24--0.2 mg/kg), dexamethasone (Dexa--4 mg/kg) or 0.9% saline for three consecutive days and killed 24 h after the last injection. Adrenal weight was significantly increased by ACTH treatment and reduced by Dexa. Concentrations of endogenous ACTH in plasma were lower in the Dexa group than in controls, and curiously, this was true in the ACTH1-24 treated group as well, probably in consequence of the increased corticosterone levels providing negative feedback at the hypothalamic-pituitary level. Corticosterone levels, as expected, were increased by the ACTH stimulus and reduced by the use of Dexa. Proliferating cell nuclear antigen immunostaining was close to zero in Dexa treated animals and low in controls. In ACTH treated rats, a significantly increased number of cells were positively stained. Positive cells were identified in both in zona glomerulosa (ZG) and zona intermedia (ZI) but many were located in the capsule. Zona fasciculata (ZF) and zona reticularis (ZR) were devoid of staining in all of these cases. We conclude that pharmacological doses of ACTH induce proliferation of capsular fibroblasts. Following descriptions by early 20th century researchers it is possible that these cells may also be stem cells and differentiate into adrenal cortex cells.

Distribution of extracellular signal-regulated protein kinases 1 and 2 in the rat adrenal and their activation by angiotensin II

“…The critical difference between these findings may depend on the presence, in our preparation, of the connective tissue capsule, which may be of key importance in adrenal proliferation (Pignatelli et al 2000(Pignatelli et al , 2002. This concept has additional significance in the light of the present finding that the primary site of stimulated cell division lies immediately beneath the connective tissue capsule.…”

Sexual dimorphism of ornithine decarboxylase in the mouse adrenal: influence of polyamine deprivation on catecholamine and corticoid levels

“…Moreover, in recent years new information (57) has accumulated supporting other functions not directly related with steroid biosynthesis for cells of the zona glomerulosa. According to these claims, glomerulosa would be the major site of adrenal cell proliferation, although it has also been suggested that stem cells from the adrenal capsula may differentiate into adrenal cortex cells (21,40). Since ODC and polyamine levels have been related with cell differentiation (20,35), one may speculate that the reduction of the relatively higher values of ODC activity present in the capsula and zona glomerulosa of murine female adrenals produced by DFMO would decrease the rate of formation of cells in zona fasciculata and zona reticularis and, hence, could diminish corticosterone biosynthesis and secretion.…”

Increased extracellular signal regulated kinases phosphorylation in the adrenal gland in response to chronic ACTH treatment

“…There have been reports that ACTH can induce increased proliferation, particularly under stress conditions (Lotfi & Armelin 1998, Pignatelli et al 2002. Notably, adrenocortical hyperplasia can occur after prolonged ACTH exposure in patients suffering from pituitary tumours producing ACTH, a situation known as Cushing's disease (CD; McNicol 2000, Imaki et al 2004).…”

“…It acts mainly upon the inner zones of the adrenal cortex -zonae fasciculata (ZF) and reticularis (ZR), while having a moderate effect upon zona glomerulosa (ZG) and capsular (Cap) cells (Fujita et al 1979, Tait et al 1980, Lehoux et al 1998, Pignatelli et al 2002.…”