Effect of the renin-angiotensin system on the exacerbation of adrenal glucocorticoid steroidogenesis in diabetic mice: Role of angiotensin-II type 2 receptor

Abstract

Prior investigation shows an increase in the activity of both hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin system (RAS) in diabetic patients. Moreover, activation of angiotensin-II type 1 receptor (AT1) has been associated with adrenal steroidogenesis. This study investigates the role of RAS on the overproduction of corticosterone in diabetic mice. Diabetes was induced by intravenous injection of alloxan into fasted Swiss-webster mice. Captopril (angiotensin-converting enzyme inhibitor), Olmesartan (AT1 receptor antagonist), CGP42112A (AT2 receptor agonist) or PD123319 (AT2 receptor antagonist) were administered daily for 14 consecutive days, starting 7 days post-alloxan. Plasma corticosterone was evaluated by ELISA, while adrenal gland expressions of AT1 receptor, AT2 receptor, adrenocorticotropic hormone receptor MC2R, pro-steroidogenic enzymes steroidogenic acute regulatory protein (StAR), and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) were assessed using immunohistochemistry or western blot. Diabetic mice showed adrenal gland overexpression of AT1 receptor, MC2R, StAR, and 11βHSD1 without altering AT2 receptor levels, all of which were sensitive to Captopril or Olmesartan treatment. In addition, PD123319 blocked the ability of Olmesartan to reduce plasma corticosterone levels in diabetic mice. Furthermore, CGP42112A significantly decreased circulating corticosterone levels in diabetic mice, without altering the overexpression of MC2R and StAR in the adrenal glands. Our findings revealed that inhibition of both angiotensin synthesis and AT1 receptor activity reduced the high production of corticosterone in diabetic mice via the reduction of MC2R signaling expression in the adrenal gland. Furthermore, the protective effect of Olmesartan on the overproduction of corticosterone by adrenals in diabetic mice depends on both AT1 receptor blockade and AT2 receptor activation.

Effects of Finerenone on Cardiovascular and Chronic Kidney Diseases: A New Weapon against Cardiorenal Morbidity and Mortality—A Comprehensive Review

“…Renin hydrolyses angiotensinogen, a protein secreted by the liver, to Angiotensin I, which in turn is converted into Angiotensin II by the activity of an angiotensin converting enzyme (ACE) [ 42 ]. Angiotensin II has a direct effect on vasoconstriction and stimulates the release of aldosterone from the adrenal cortex [ 43 ]. Aldosterone binds the mineralocorticoid receptor (MR) located in the distal tubules and collector ducts, inducing increased sodium reabsorption and potassium secretion through an increased concentration and activity of the epithelial sodium channels and the Na + /K + ATPase pump [ 43 ].…”

“…Angiotensin II has a direct effect on vasoconstriction and stimulates the release of aldosterone from the adrenal cortex [ 43 ]. Aldosterone binds the mineralocorticoid receptor (MR) located in the distal tubules and collector ducts, inducing increased sodium reabsorption and potassium secretion through an increased concentration and activity of the epithelial sodium channels and the Na + /K + ATPase pump [ 43 ]. The mineralocorticoid receptor is a member of the nuclear hormone receptors, a group of receptors which, upon the binding of their ligand, act as transcription factors and play a crucial role in the pathogenesis of cardiovascular and renal diseases.…”

The Role of the Adrenal–Gut–Brain Axis on Comorbid Depressive Disorder Development in Diabetes

“…We and others have shown that diabetic animals exhibit high levels of ACTH and corticosterone in the circulation [30][31][32][33], and an impairment in the negative feedback of the HPA axis [34]. We previously demonstrated that the exacerbation of glucocorticoid production by diabetic animals was related to overexpression of ACTH receptor (MC2R) and steroidogenic enzymes, including steroidogenic acute regulatory protein (StAR) and 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1), in the adrenal gland [33,35], while the failure in the negative feedback of the HPA axis was associated with a downregulation of GRs and mineralocorticoid receptors (MRs) in the pituitary. In addition, we showed that the reduction in the GR expression in the pituitary gland of diabetic rats occurred 24 h after the onset of hyperglycemia, suggesting that the lack of glycemic control in diabetics may be involved with the downregulation of GR in the pituitary gland [33,36].…”

“…Furthermore, the inhibitory effect of rosiglitazone on the hyperactivity of the HPA axis observed in diabetic rats was related to an upregulation of PI3K expression in the pituitary and adrenal glands. However, the exact mechanisms by which CGP42112A reduced the exacerbation of corticosterone production by adrenal glands of diabetic mice still remain elusive [35,36]. As observed in the adrenal gland, diabetic patients and animals showed a pro-inflammatory profile in their circulation [37,38].…”