Pancreatic acinar-specific overexpression of Reg2 gene offered no protection against either experimental diabetes or pancreatitis in mice
Pancreatic acinar-specific overexpression of Reg2 gene offered no protection against either experimental diabetes or pancreatitis in mice
复制标题
Reg2 基因的胰腺腺泡特异性过度表达无法预防小鼠实验性糖尿病或胰腺炎
DOI：
10.1152/ajpgi.00500.2009
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发表时间：
2010-08-01
影响因子：
4.5
通讯作者：
Liu, Jun-Li
中科院分区：
文献类型：
--
作者：
Li, Bing;Wang, Xiao;Liu, Jun-Li
李B，王X，刘俊龙.胰腺腺泡特异性过表达Reg 2基因对小鼠实验性糖尿病或胰腺炎均无保护作用。美国生理学杂志胃肠和肝脏生理学299：G413-G421，2010年。首次发表于2010年5月20日; doi：10.1152/ajpgi.00500.2009。（1）-Reg蛋白质通常在胰腺腺泡细胞中表达，并且这些蛋白质中的几种的水平在损伤内分泌或外分泌胰腺时被显著诱导。已经确定，Reg 1和胰岛再生相关蛋白[INGAP，Reg 3 δ]促进内分泌胰岛细胞的生长或再生。最近的报告表明，Reg 2是一种自身抗原，通常在胰岛β细胞中表达。Reg 2在体外过表达对胰岛素瘤细胞具有保护作用。Reg 3 α过表达增加细胞周期蛋白D1和CDK 4水平和胰岛素瘤细胞的增殖率。INGAP的腺泡特异性过表达增加了β细胞质量，并保护动物免受链脲佐菌素诱导的糖尿病。此外，Reg 2基因表达诱导胰腺炎。我们假设Reg 2是一种分泌蛋白，可促进胰腺内分泌和外分泌细胞的生长、存活和/或再生。为了测试其有效性，我们使用弹性蛋白酶-1启动子（Ela-Reg 2）来开发Reg 2基因的腺泡细胞特异性过表达。Western印迹分析、实时PCR和免疫组织化学显示，正常野生型小鼠胰腺中几乎检测不到内源性Reg 2水平，Ela-Reg 2小鼠胰腺中的Reg 2水平增加，其类似于或高于实验性糖尿病或胰腺炎中诱导的Reg 2水平。与野生型同窝小鼠相比，Ela-Reg 2小鼠的生长、血糖和胰岛素水平以及葡萄糖耐量均正常;胰腺组织学显示内分泌或外分泌组织无变化。Reg 2基因的腺泡特异性过表达对链脲佐菌素诱导的β细胞损伤和糖尿病、高血糖和体重减轻没有保护作用，在3个月内恢复葡萄糖稳态和胰岛功能也没有优势。此外，血清淀粉酶水平和胰腺组织化学显示Reg 2过表达不能保护腺泡细胞对抗雨蛙肽诱导的急性胰腺炎。与INGAP或Reg 3 β相反，Reg 2的外分泌过表达对内分泌或外分泌胰腺没有提供保护，这表明Reg蛋白家族具有明显的亚型特异性。
Li B, Wang X, Liu JL. Pancreatic acinar-specific overexpression of Reg2 gene offered no protection against either experimental diabetes or pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 299: G413-G421, 2010. First published May 20, 2010; doi: 10.1152/ajpgi.00500.2009.(1)-Reg proteins are normally expressed in pancreatic acinar cells, and the level of several of these proteins was significantly induced upon damage to the endocrine or exocrine pancreas. It has been established that Reg1 and pancreatic islet neogenesis-associated protein [INGAP, Reg3 delta] promote the growth or regeneration of the endocrine islet cells. Recent reports suggest that Reg2 is an autoantigen normally expressed in islet beta-cells. Reg2 overexpression in vitro offered protection to insulinoma cells. Overexpressed Reg3 alpha increased cyclin D1 and CDK4 levels and the rate of proliferation in insulinoma cells. Acinar-specific overexpression of INGAP increased beta-cell mass and protected the animals from streptozotocin-induced diabetes. Moreover, Reg2 gene expression was induced during pancreatitis. We hypothesized that Reg2 is a secreted protein that promotes the growth, survival, and/or regeneration of pancreatic endocrine and exocrine cells. To test its effectiveness, we used elastase-1 promoter (Ela-Reg2) to develop an acinar cell-specific overexpression of the Reg2 gene. Western blot analysis, real-time PCR, and immunohistochemistry revealed barely detectable levels of endogenous Reg2 in the pancreas of normal wild-type mice and increased Reg2 levels in the pancreas of Ela-Reg2 mice that were similar to or higher than Reg2 levels induced in experimental diabetes or pancreatitis. Compared with wild-type littermates, growth, blood glucose and insulin levels, and glucose tolerance were normal in Ela-Reg2 mice; pancreatic histology revealed no change in endocrine or exocrine tissues. Acinar-specific overexpression of the Reg2 gene offered no protection against streptozotocin-induced beta-cell damage and diabetes, in hyperglycemia and weight loss, and no advantage in restoring glucose homeostasis and islet function within 3 mo. Furthermore, serum amylase level and pancreatic histochemistry showed that Reg2 overexpression did not protect acinar cells against caerulein- induced acute pancreatitis. In contrast to INGAP or Reg3 beta, exocrine overexpression of Reg2 offered no protection to the endocrine or exocrine pancreas, indicating clear subtype specificities of the Reg family of proteins.