胰腺局部Mas调节葡萄糖稳态及其分子机制研究

The actions of angiotensin - (1-7)-Mas receptor axis counterbalance those of Ang-Ⅱ. Our data showed Mas protein was detected in both endocrine tissue and exocrine tissue of pancreas. The changes of Mas in islets were detected earlier than ACE2 in OLETF rat in pancreas with diabetes. The binding of Ang-(1-7) and Mas can stimulate the islet cells to secrete insulin, and caused a significant stimulation of mRNA and protein expression of GLUT-2. On the contrary, our result showed a reduction in TGF-β1 mRNA and protein expression. Meantime, we establish the evidence for expression of CFTR protein in mouse pancreatic islets. These results provide the evidence for putative role of Mas receptor in pancreas. However, the possible molecular mechanism of Mas receptor in glucose homeostasis in pacreas is unclear. We hypothesis that Mas can regulate the glucose homeostasis, probably due to its enhancing the ability to intake glucose, also regulate MAPKs and CFTR pathway stimulated by TGF-β1. Using the animal model, we aimed to investigate the changes of glucose homeostasis in Mas-deficient mice. On the other hand, in vivo and in vitro study, after the cells were preincubated with Ang-(1-7) or A779, we investigate the effect of Mas on insulin secretion. Also we investigate the potential role of Mas on calcium pathway regulated by GLUT-2 and MAPKs and CFTR pathway stimulated by TGF-β1. These findings might provide a new vision on pancreatic disease .

Ang-（1-7）通过Mas在体内发挥拮抗血管紧张素-Ⅱ作用。我们研究发现Mas在大鼠胰腺表达，OLETF糖尿病大鼠胰岛细胞Mas的改变先于ACE2变化。Mas与Ang-(1-7)结合可促进胰岛细胞分泌胰岛素、上调GLUT-2表达、减少TGF-β1生成，胰岛细胞表达CFTR。但胰腺局部Mas对葡萄糖糖稳态调节的作用机制尚不清楚。本课题假设：胰腺局部Mas参与葡萄糖稳态调节，并可能通过调控胰岛细胞葡萄糖摄取、MAPK通路及离子通道等发挥作用。本课题拟观察Mas敲除小鼠糖代谢及胰岛素水平的改变；经Mas激动剂Ang(1-7)及其拮抗剂A779干预，体内、体外研究探讨Mas对胰岛细胞胰岛素分泌、GLUT-2调控的Ca2+ 通道、TGF-β1激活的MAPKs（ERK1/2, SAPK/JNK, and p38 MAPK）及CFTR离子通道的影响，以论证假说，并为研究胰腺疾病的潜在方向提供线索。

Ang-（1-7）通过Mas在体内发挥拮抗血管紧张素-Ⅱ作用。但胰腺局部Mas对葡萄糖糖稳态调节的作用机制尚不清楚。本课题假设：胰腺局部Mas参与葡萄糖稳态调节，并可能通过调控胰岛细胞葡萄糖摄取、MAPK通路及离子通道等发挥作用。本课题观察糖尿病大鼠及Mas敲除小鼠糖代谢及胰岛素水平的改变；经Mas激动剂Ang(1-7)及其拮抗剂A779干预，体内、体外研究探讨Mas对胰岛细胞胰岛素分泌、GLUT-2调控的Ca2+通道、TGF-β1激活的MAPKs及CFTR离子通道的影响。我们研究发现Mas在大鼠胰腺表达，糖尿病大鼠胰岛细胞Mas的表达下降，Mas缺失鼠呈现糖耐量异常，Mas与Ang-(1-7)结合可促进胰岛细胞分泌胰岛素。胰岛细胞表达CFTR。胰腺局部Mas与糖代谢存在密切关系，可能通过葡萄糖转运、TGF-β1调控的CFTR离子通道等环节发挥作用，在葡萄糖稳态中可能具有良性调节作用，为研究胰腺疾病的潜在方向提供线索。