Aldosterone induces clonal β-cell failure through glucocorticoid receptor.
Aldosterone induces clonal β-cell failure through glucocorticoid receptor.
复制标题
醛固酮通过糖皮质激素受体诱导克隆性β细胞衰竭
DOI：
10.1038/srep13215
复制
发表时间：
2015-08-19
影响因子：
4.6
通讯作者：
Han X
中科院分区：
文献类型：
--
作者：
Chen F;Liu J;Wang Y;Wu T;Shan W;Zhu Y;Han X
醛固酮过多引起外周组织胰岛素抵抗，直接损害克隆性β细胞功能。本研究旨在探讨醛固酮对克隆性β细胞损伤的分子机制。正如预期的那样，醛固酮诱导细胞凋亡和β细胞功能障碍，包括胰岛素合成和分泌的受损，其被糖皮质激素受体（GR）拮抗剂或GR特异性siRNA逆转。然而，盐皮质激素受体（MR）拮抗剂或MR特异性siRNA对醛固酮诱导的克隆β细胞损伤没有影响。此外，醛固酮还能显著降低MafA的表达和活性，并以GR依赖的方式激活JNK和p38 MAPK。此外，JNK抑制剂（SP 600125）和/或p38抑制剂（SB 203580）可阻断醛固酮对MafA表达和活性的影响。重要的是，JNK 1或p38的过表达逆转了GR拮抗剂对MafA表达和活性降低的保护作用。此外，醛固酮通过激活JNK和p38分别在转录和转录后水平抑制MafA表达。因此，MafA的过表达增加了暴露于醛固酮的克隆β细胞中胰岛素的合成和分泌，并减少了细胞凋亡。这些发现将醛固酮鉴定为通过GR-MAPK-MafA信号传导途径起作用的克隆β细胞衰竭的诱导剂。
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.