Abstract
In situ cortisol excess was previously reported to promote cellular senescence, a cell response to stress, in cortisol-producing adenomas (CPA). The aim of this study was to explore senescence pathways in aldosterone-producing cells and related disorders, and the influence of aldosterone overproduction on in situ senescence. We analyzed 30 surgical cases of aldosterone-producing adenoma (APA), 10 idiopathic hyperaldosteronism (IHA) and 19 normal adrenals (NA). CYP11B2 and senescence markers p16 and p21 were immunolocalized in all those cases above and results were correlated with histological/endocrinological findings. In the three cohorts examined, the zona glomerulosa (ZG) was significantly more senescent than other corticosteroid-producing cells. In addition, the ZG of adjacent non-pathological adrenal glands of APA and IHA had significantly higher p16 expression than adjacent non-pathological zona fasciculata (ZF), reticularis (ZR) and ZG of NA. In addition, laboratory findings of primary aldosteronism (PA) were significantly correlated with p21 status in KCNJ5-mutated tumors. Results of our present study firstly demonstrated that non-aldosterone-producing cells in the ZG were the most senescent compared to other cortical zones and aldosterone-producing cells in PA. Therefore, aldosterone production, whether physiological or pathological, could be maintained by suppression of cell senescence in human adrenal cortex.
Highlights
Cellular senescence is a complex, anti-proliferative cellular process which generally leads the cells to a state of irreversible growth arrest in response to different stressors, in order to remove the damaged cells from the homeostatic tissue environment [1]
Most senescence-inducing stressors have been reported to activate either the p16Ink4a or p53/p21 intracellular signaling, which have emerged as possible biomarkers of cellular senescence [4,5]. p16Ink4a was reported to be mostly involved in the senescence-induction process and p21 in the maintenance of cell cycle arrest [6]
In aldosteroneproducing adenoma (APA), p16 was predominantly immunolocalized in Adj.zona glomerulosa (ZG) compared to Adj.zona fasciculata (ZF) (p = 0.022), Adj.ZR (p < 0.001) and aldosterone-producing lesion (APA p < 0.001). p21-immunoreactivity in APA cases was significantly higher in Adj.ZG than APA (p = 0.002), but not in Adj.ZF and Adj.ZR
Summary
Cellular senescence is a complex, anti-proliferative cellular process which generally leads the cells to a state of irreversible growth arrest in response to different stressors, in order to remove the damaged cells from the homeostatic tissue environment [1]. Recent studies demonstrated that cellular mechanisms of senescence were more complex than previously considered and involved numerous different intracellular signal transduction pathways [3]. Most senescence-inducing stressors have been reported to activate either the p16Ink4a or p53/p21 intracellular signaling, which have emerged as possible biomarkers of cellular senescence [4,5]. P16Ink4a was reported to be mostly involved in the senescence-induction process and p21 in the maintenance of cell cycle arrest [6]. Aldosterone, the main mineralocorticoid, is biosynthesized in ZG cells in response to Angiotensin II or elevated plasmatic potassium concentration [9]
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