醛固酮介导胰岛微循环内皮间充质化的机制研究

2型糖尿病（T2DM）病人和动物胰岛均存在不同程度纤维化，现已证实胰岛纤维化可直接导致胰岛结构和功能受损。内皮细胞转化而来的成纤维细胞，即内皮细胞间充质化，是导致器官纤维化的重要原因，但胰岛微循环是否也存在内皮间充质化尚不明确。研究发现高醛固酮血症与T2DM的胰岛功能损伤密切相关，但机制不明，我们预实验发现醛固酮可通过其受体诱导胰岛微循环内皮细胞间充质化及PARP-1的活化。而我们的既往研究已证实PARP-1在胰岛微血管内皮氧化应激的损伤中也发挥着重要作用且可调控人主动脉内皮间充质化。因此我们提出“醛固酮可通过PARP-1通路促进胰岛微血管内皮间充质化影响胰岛β细胞功能”的假设。本研究将采用内皮特异性醛固酮受体敲除的db/db小鼠为模型，从分子、细胞、组织及动物多层次观察醛固酮对胰岛微循环内皮间充质化的影响，并探索醛固酮受体拮抗剂在其中发挥的治疗作用，以期为临床T2DM的治疗提供新的思路。

Type 2 diabetes (T2DM) patients and animals have varying degrees of islet fibrosis. Accumulative studies showed that islet fibrosis could damage normal islet structures and functions. Studies have confirmed that endothelial to mesenchymal transition, EndMT, plays a very important role in organ fibrosis. However, whether there is EndMT in islet is still unknown. Previous studies suggest that high aldosterone is closely related to islet dysfunction in T2DM, though the mechanism is still unclear. Our pre-experimental data showed that aldosterone could induce islet microvascular endothelial to mesenchymal transition and PARP-1 activation in vitro. Moreover, our previous study demonstrated that PARP-1 activation could regulate EndMT in human aortic endothelial cells and facilitate islet microvascular endothelial oxidative stress injury. Therefore, we hypothesized that aldosterone may promote islet microvascular endothelial cells to mesenchymal transition via PARP-1 pathway, which may eventually contribute to diabetic islet dysfunction. This study will use endothelial-specific aldosterone receptor knockout db / db mice as a model to explore whether aldosterone can induce islet microvascular endothelial cells to mesenchymal transition and the potential mechanisms by which aldosterone regulates islet EndMT. The results may provide new strategies for the treatment of T2DM.