关键词: 糖尿病肾病, 利拉鲁肽, 内质网应激

Abstract: Objective To investigate the effect of liraglutide on ameliorating renal tissue damage of diabetic rats by inhibiting kinase R-like ER kinase (PERK)/phosphorylation of eukaryotic initiation factor-2α(eIF2α)/activated transcription factor 4 (ATF4) /C/ EBP-homologous protein (CHOP) pathway mediated by endoplasmic reticulum stress and its mechanism. 
Methods A rat model of type 2 diabetes mellitus (T2DM) was induced by a high-carbohydrate, high-fat diet and intraperitoneal injection of low-dose Streptozotocin (STZ) (30 mg/kg). At 5 weeks after STZ injection, diabetic rats were randomly treated with subcutaneous injection or no subcutaneous injection of Liraglutide (0.2 mg/kg/12 h) for 8 weeks. The rats were divided into NC group, DN group and DN+Lira group. Diabetes-related physical and biochemical indexes, renal histopathology and ultrastructural changes were measured. The levels of superoxide diamutase (SOD), reactive oxygen species (ROS) level, malondialdehyde (MDA) and myeloperoxidase (MPO) were detected by corresponding kits, respectively. The expression of endoplasmic reticulum stress-related proteins and PERK/eIF2α/ATF4/CHOP pathway were analyzed by Western blotting. 
Results At 5 weeks after STZ injection, the fasting blood glucose (FBG) in the DN group was consistently higher than that in the NC group. At 13 weeks after STZ injection (8 weeks after Liraglutide administration), the DN group and DN+Lira group showed significantly higher FBG, hemoglobin A1c (HbA1c), renal body mass index, serum creatinine (SCr), and blood urea nitrogen (BUN) compared with the NC group, but significantly lower body weight compared with the NC group; The FBG, HbA1c, renal body mass index, SCr, and BUN in the DN+Lila group were significantly lower than those in the DN group (P＜0.05). At 5 weeks after STZ injection (0 week after Liraglutide administration), the urinary albumin/creatinine ratio (ACR) in the DN group and DN+Lira group was significantly higher than that in the NC group, and the difference was statistically significant (P＜0.05). At the end of the study (8 weeks after administration of Liraglutide), the urinary ACR in the DN group and DN+Lira group was significantly higher than that in the NC group, while the urinary ACR in the DN+Lila group was significantly lower than that in the DN group (P＜0.05). The mesangial matrix index of DN group and DN+Lira group was significantly higher than that of NC group, while the mesangial matrix index of DN+Lira group was significantly lower than that of DN group, with statistical significance (P＜0.05). The protein levels of glucose regulated protein 78 (GRP78), phosphorylated inositol requiring enzyme 1 α (p-IRE1 α), activating transcription factor 6 (ATF6), and caspase-12 in the DN group were significantly higher than those in the NC group, while the protein levels of GRP78, p-IRE1 α, ATF6, and Caspase-12 in the DN+Lira group were significantly lower than those in the DN group (P＜0.05). The levels of MDA, ROS, and MPO in the DN group were significantly higher than those in the NC group, while the levels of SOD were lower than those in the NC group. In the DN+Lira group, the levels of MDA, ROS, and MPO were significantly lower than those in the DN group, and the levels of SOD were higher than those in the DN group (P＜0.05). The levels of p-PERK, p-eIF2 α, ATF4, and CHOP in the renal cortex of the DN group were significantly higher than those of the NC group, while the levels of p-PERK, p-eIF2 α, p-ATF4, and CHOP in the renal cortex of the DN+Lira group were significantly lower than those of the DN group (P＜0.05). 
Conclusion Liraglutide may play a renal protective role by inhibiting the PERK/eIF2α/ATF4/CHOP pathway mediated by endoplasmic reticulum stress. 

Key words: diabetic kidney disease, liraglutide, endoplasmic reticulum stress