基于GH/IGF-1轴糖尿病肾病大鼠Snail 1通路及TEMT的研究

A relationship has not been noted between the activity of the growth hormone (GH) / insulin-like growth factor 1 (IGF-I) axis and Snail 1 in diabetic nephropathy (DN). Previous study, we first reported that the Snail 1 promoted tubular epithelial cell-myofibroblast trans-differentiation (TEMT) in the model of DN. To investigate the mechanism of the Snail 1-induced the GH/IGF-1 activation for the TEMT in DN, streptozotoein-induced diabetic rats will be randomly divided into three groups: Control group, DN group and DN rats intervened with the inhibitor of IGF-1 receptor (IGF-1R group). The serum concentrations of GH and IGF-1, serum creatinine(Scr) of rats are measured. PAS and Masson staining will be used to observe the renal pathological changes. Immunohistochemical staining and Western blot will be employed to derermine the espressions of IGF-1, Snail 1, E-cadherin, and fibronectin(FN) proteins in renal tissues. Rat renal tubular epithelial cells will be collected with grinding and digesting methods from each group, and IGF-1 will be transfected in to renal tubular epithelial cells. Then the mRNA and protein of IGF-1, Snail 1 and E-cadherin will be detected. .The relation of the GH/ IGF-1 axis and Snail 1 in the pathogenesis of DN rats will be investigated the impact of GH/IGF-1 on Snail 1 in renal tubular epithelial cells after transfection. Also the serum concentrations of GH and IGF-1 and the expression of IGF-1 and Snail 1 mRNA and protein in renal tissues will be measured. We will explore whether the GH/IGF-1 axis promotes the development of the TEMT through the Snai l pathways by observing the pathological changes and detecting the expression of E-cadherin and FN in renal tissues of DN rats. Then the GH/IGF-1 axis will be restrained by the inhibitor of IGF-1R and the renal histomorphological features and the expression of Snail 1, E-cadherin and FN will be tested. .In our study, we will investigate the relationship between the GH/IGF-1 axis and Snail 1 in DN rats, the impact of GH/IGF-1 axis on TEMT wether through Snai l pathway. In order to identify the GH/IGF-1 axis up-regulates TEMT through Snail 1 in DN rats, we use the inhibitor of IGF-1R to restrain the GH/IGF-1 axis. The foundings will provide a novel mechanism for GH/IGF-1 axis's role in the pathogenesis of DN, and offer the possibility of targeting the GH/IGF-1 axis for the prevention and treatment of DN.

既往研究发现胰岛素样生长因子（IGF-1）能使上皮细胞内 E-钙粘蛋白的表达降低，促进肾小管上皮细胞间充质转分化（TEMT） 的快速转化，导致肾组织纤维化。而IGF-1的水平受到生长因子（GH）的调控。我们首次研究观察到锌指转录因子1（Snail 1）的表达在糖尿病肾病（DN）大鼠肾组织中显著上调，Snail 1与E-钙粘蛋白表达呈显著负相关，表明Snail 1触发肾小管上皮细胞EMT，是DN发生、发展的主要原因之一。因此，我们拟建立糖尿病肾病大鼠模型，探讨GH/IGF-1轴与Snail 1的相关性，GH/IGF-1轴是否通过Snail 1通路促进肾脏TEMT的转化，及IGF-1受体拮抗剂的干预作用。研究结果将为DN肾纤维化的发病机制提供新的循证医学证据及治疗靶点。

既往研究发现胰岛素样生长因子（IGF-1）能使上皮细胞内 E-钙粘蛋白的表达降低，促进肾小管上皮细胞间充质转分化（TEMT） 的快速转化，导致肾组织纤维化。而IGF-1的水平受到生长因子（GH）的调控。我们首次研究观察到锌指转录因子1（Snail 1）的表达在糖尿病肾病（DN）大鼠肾组织中显著上调，Snail 1与E-钙粘蛋白表达呈显著负相关，表明Snail 1触发肾小管上皮细胞EMT，是DN发生、发展的主要原因之一。因此，我们拟建立糖尿病肾病大鼠模型，探讨GH/IGF-1轴与Snail 1的相关性，并证实了GH/IGF-1轴是否通过Snail 1通路促进肾脏TEMT的转化，及IGF-1受体拮抗剂的干预作用能改善DN肾脏纤维化。研究结果将为DN肾纤维化的发病机制提供新的循证医学证据及治疗靶点。