Aldosterone from endometrial glands is benefit for human decidualization

Abstract

Local renin-angiotensin system (RAS) in female reproductive system is involved in many physiological and pathological processes, such as follicular development, ovarian angiogenesis, ovarian, and endometrial cancer progress. However, studies on the functional relevance of RAS in human endometrium are limited, especially for reninangiotensin-aldosterone system (RAAS). In this study, we defined the location of RAS components in human endometrium. We found that angiotensin II type-1 receptor (AT 1 R) and aldosterone synthase (CYP11B2), major components of RAAS, are specifically expressed in endometrial gland during mid-secretory phase. Aldosterone receptor, mineralocorticoid receptor (MR), is elevated in stroma in mid-secretory endometrium. In vitro, MR is also activated by aldosterone during decidualization. Activated MR initiates LKB1 expression, followed by phosphorylating of AMPK that stimulates PDK4 expression. The impact of PDK4 on decidualization is independent on PDHE1α inactivation. Based on co-immunoprecipitation, PDK4 interacts with p-CREB to prevent its ubiquitination for facilitating decidualization via FOXO1. Restrain of MR activation interrupts LKB1/p-AMPK/PDK4/p-CREB/FOXO1 pathway induced by aldosterone, indicating that aldosterone action on decidualization is mainly dependent on MR stimulation. Aldosterone biosynthesized in endometrial gland during mid-secretory phase promotes decidualization via activating MR/LKB1/p-AMPK/PDK4/p-CREB/FOXO1 signaling pathway. This study provides the valuable information for understanding the underlying mechanism during decidualization.

LKB1 alleviates high glucose‑ and high fat‑induced inflammation and the expression of GnRH and sexual precocity‑related genes, in mouse hypothalamic cells by activating the AMPK/FOXO1 signaling pathway

“…As the upstream kinase capable of AMPK, LKB1 can activate AMPK through the phosphorylation of p-AMPKα of its catalytic α subunit ( 24 ). In the endometrial glands, LKB1 can promote the phosphorylation of AMPK, thereby increasing the activity of FOXO1 ( 10 ). A clear reduction in GnRH release is observed following the elevation in the FOXO1 activity in the hypothalamus ( 11 ).…”

“…In recent years, LKB1 has been reported to be associated with obesity and LKB1 knockout in the hypothalamus has been shown to intensify susceptibility to obesity in mice administered with a high-fat (HF) diet, accompanied by a deterioration of hypothalamic inflammation and downregulation of neuronal expression ( 9 ). In the endometrial glands, LKB1 can promote the phosphorylation of AMP-activated protein kinase (AMPK), thereby increasing the activity of forkhead box protein O1 (FOXO1) ( 10 ). A clearly reduced release of GnRH is observed following the elevation of FOXO1 activity in the hypothalamus ( 11 ).…”

Caveolin-1 Regulation and Function in Mouse Uterus during Early Pregnancy and under Human In Vitro Decidualization

“…Briefly, human stromal cells were cultured in DMEM/F12 supplemented with 10% cFBS at 37 °C and 5% CO 2 . In vitro decidualization was performed as previously described [ 54 ]. Briefly, stromal cells were treated with 1 μM medroxyprogesterone and 0.5 mM dibutyryl cAMP to induce decidualization.…”

The Plasminogen Activator System, Glucocorticoid, and Mineralocorticoid Receptors in the Primate Endometrium During Artificial Menstrual Cycles

“…Adrenal corticoids have been studied in previous reports and their receptors have been identified in luminal and glandular epithelial cells, both in undifferentiated and decidualized stromal cells, smooth muscle cells surrounding blood vessels, and in the endothelial cells [7][8][9]34]. The GR has been demonstrated in human stromal cells, vascular endothelial cells, uterine natural killer cells, and mast cells similar to estrogen, progesterone, and androgen receptors [7][8][9]35]. We have characterized the localization of MR and GR in this study, which generally show similar expression and distribution of each receptor in the macaque stroma across the hormonal cycles.…”

“…6 (A) Immunohistochemical staining for GR in monkey tonsil as positive control (B) Immunohistochemical staining for GR with no primary antibody as negative control (C-K) Immunolocalization of GR in endometrial vascular (arrows), glandular and stromal cells during artificial hormonal cycles in macaques for effects of cortisol and aldosterone on endometrial morphology despite both the GR and MR being present in the endometrial stroma. Aldosterone, a mineralocorticoid, has been shown to be involved in decidualization but most likely via the renin-angiotensin-aldosterone system, not the MR [35]. Progesterone receptor modulators such as ulipristal acetate have limited binding to the GR and do not interact with the MR [38].…”