Aldosterone directly affects apelin expression and secretion in adipocytes

Abstract

There is a high incidence of metabolic syndrome among patients with primary aldosteronism (PA), which has recently been associated with an unfavorable cardiometabolic profile. However, the underlying mechanisms have not been clarified in detail. Characterizing aldosterone (Ald) target genes in adipocytes will help us to elucidate the deleterious effects associated with excess Ald. Apelin, a novel adipokine, exerts beneficial effects on obesityassociated disorders and cardiovascular homeostasis. The objective of this study was to investigate the effects of high Ald levels on apelin expression and secretion and the underlying mechanisms involved in adipocytes. In vivo, a single-dose Ald injection acutely decreased apelin serum levels and adipose tissue apelin production, which demonstrates a clear inverse relationship between the levels of plasma Ald and plasma apelin. Experiments using 3T3-L1 adipocytes showed that Ald decreased apelin expression and secretion in a time-and dose-dependent manner. This effect was reversed by glucocorticoid receptor (GR) antagonists or GR (NR3C1) knockdown; furthermore, putative HREs were identified in the apelin promoter. Subsequently, we verified that both glucocorticoids and mineralocorticoids regulated apelin expression through GR activation, although no synergistic effect was observed. Additionally, detailed potential mechanisms involved a p38 MAPK signaling pathway. In conclusion, our findings strengthen the fact that there is a direct interaction between Ald and apelin in adipocytes, which has important implications for hyperaldosteronism or PA-associated cardiometabolic syndrome and hoists apelin on the list of potent therapeutic targets for PA. Key Words" aldosterone " apelin " 3T3-L1 adipocyte " glucocorticoid receptor " p38 MAPK

Mineralocorticoid Receptor Blockade Improves Insulin Sensitivity in the Rat Heart and a Possible Molecular Mechanism

“…In contrast, one study demonstrated that aldosterone treatment results in the dysregulation of proinflammatory cytokines and adiponectin through MRs in adipocytes [24]. Furthermore, MR antagonism effectively reverses the dysregulation of cytokine expression levels [27]. In our observations, aldosterone decreased adiponectin and glucose uptake in cardiomyocytes, but the MR antagonist prevented these effects.…”

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…Additional studies have determined that hypoxia-inducible apelin up-regulation is mediated by HIF1a at a HRE within the APLN intron (conserved in rat and mouse apelin genes) between C813 and C826 bp (Eyries et al 2008), indicating that apelin may play a role in the homeostatic response to low oxygen levels. Insulin has also been shown to increase the expression of apelin in human and mouse adipocytes, via PI3K, protein kinase C (PKC), mitogen-activated and ERK kinase (MAPK) 1 (Boucher et al 2005) and HIF1a (Glassford et al 2007), while aldosterone has been shown to decrease the expression of apelin in 3T3-L1 adipocytes via the p38 MAPK pathway (Jiang et al 2013). Furthermore, studies on white adipocytes have found that the peroxisome proliferator-activated receptor g co-activator 1a also up-regulates the expression of apelin, possibly indicating that apelin plays a role in energy metabolism (Mazzucotelli et al 2008), while recently in diabetic rats, ghrelin has been reported to reduce apelin mRNA synthesis and release into the lumen (Coskun et al 2013).…”

Effects of antihypertensive treatment on plasma apelin, resistin, and visfatin concentrations

“…9 It has been shown that apelin expression is increased by tumor necrosis factor α (TNF-α) 10 and hypoxia-inducible factor 1-α 11 (HIF-1α) and decreased by aldosterone. 12 A modest, although unclear, role in the control of food intake has been described for apelin, and activation of the APJ has been shown to exert a stimulatory effect on gastric and endothelial cell proliferation. 13 Further studies on the physiology of apelin are needed to provide new insights into glucose homeostasis as well as new therapies for cardiovascular complications.…”