Abstract
Aldosterone excess causes insulin resistance in peripheral tissues and directly impairs the function of clonal β-cell. The aim of this study was to investigate the molecular mechanisms involved in the aldosterone-induced impairment of clonal β-cells. As expected, aldosterone induced apoptosis and β-cell dysfunction, including impairment of insulin synthesis and secretion, which were reversed by Glucocorticoid receptor (GR) antagonists or GR-specific siRNA. However, mineralocorticoid receptor (MR) antagonists or MR-specific siRNA had no effect on impairment of clonal β-cells induced by aldosterone. Besides, aldosterone significantly decreased expression and activity of MafA, while activated JNK and p38 MAPK in a GR-dependent manner. In addition, JNK inhibitors (SP600125) and/or p38 inhibitors (SB203580) could abolish the effect of aldosterone on MafA expression and activity. Importantly, overexpression of JNK1 or p38 reversed the protective effect of a GR antagonist on the decrease of MafA expression and activity. Furthermore, aldosterone inhibits MafA expression at the transcriptional and post-transcriptional level through activation of JNK and p38, respectively. Consequently, overexpression of MafA increased synthesis and secretion of insulin, and decreased apoptosis in clonal β-cells exposed to aldosterone. These findings identified aldosterone as an inducer of clonal β-cell failure that operates through the GR-MAPK-MafA signaling pathway.
Highlights
Oncogene homologue A) is an activator of insulin synthesis and secretion as well as a key regulator of β-cell survival[15,16]
Aldosterone significantly decreased insulin secretion from Min[6] cells after stimulation with 20 mmol/l glucose or 50 mmol/l KCl in a dose-dependent manner when compared to the non-treated control
We further examined the role of MAPK in the GR-mediated decrease of MafA expression and transcriptional activity by cotransfecting Min[6] cells with JNK1, JNK2 or p38 plasmids in combination with the MAREs-luc reporter plasmid followed by treatment with aldosterone and/or GR antagonist RU486
Summary
Oncogene homologue A) is an activator of insulin synthesis and secretion as well as a key regulator of β-cell survival[15,16]. Expression and/or transcriptional activity of MafA are decreased, which results in β-cells apoptosis and dysfunction[17]. Several factors, such as high levels of glucose, palmitate, and proinflammatory cytokines, inhibited MafA expression in β-cells[18,19]. A growing body of evidence indicated that activation of MAPKs signaling is involved in the regulation of MafA expression[20,21]. We found that aldosterone stimulated GR expression and increased JNK and p38 phosphorylation level while decreasing MafA level and activity. We tested the hypothesis that aldosterone directly induces β-cell dysfunction and apoptosis by promoting the GR regulation of MafA expression via MAPK activation
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