Cao Aili, Wang Li, Chen Xia, Guo Hengjiang, Chu Shuang, Zhang Xuemei, Peng Wen
Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine.
Biol Pharm Bull. 2016 Aug 1;39(8):1300-8. doi: 10.1248/bpb.b16-00094. Epub 2016 May 18.
Oxidative stress has a great role in diabetes and diabetes induced organ damage. Endoplasmic reticulum (ER) stress is involved in the onset of diabetic nephropathy. We hypothesize that ER stress inhibition could protect against kidney injury through anti-oxidative effects. To test whether block ER stress could attenuate oxidative stress and improve diabetic nephropathy in vivo and in vitro, the effect of ursodeoxycholic acid (UDCA), an ER stress inhibitor, on spontaneous diabetic nephropathy db/db mice, ER stress inducer or high glucose-triggered podocytes were studied. Mice were assigned to 3 groups (n=6 per group): control group (treated with vehicle), db/db group (treated with vehicle), and UDCA group (db/db mice treated with 40 mg/kg/d UDCA). After 8 weeks treatment, mice were sacrificed. Blood and kidneys were collected for the assessment of albumin/creatinine ratio, blood urea nitrogen (BUN), serum creatinine (SCr), insulin, total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C), oxidized LDL-C, high density lipoprotein cholesterol (HDL-C), non-esterified fatty acid (NEFA), superoxide dismutase (SOD), catalase (CAT), methane dicarboxylic aldehyde (MDA), the expressions of SOD isoforms and glutathione peroxidase 1, as well as histopathological examination. In addition, generation of reactive oxygen species (ROS) was detected by 2'7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence. The results showed that UDCA alleviated renal ER stress-evoked cell death, oxidative stress, renal dysfunction, ROS production, upregulated the expression of Bcl-2 and suppressed Bax in vivo and in vitro. Hence, inhibition ER stress diminishes oxidative stress and exerts renoprotective effects.
氧化应激在糖尿病及其所致器官损伤中起重要作用。内质网（ER）应激参与糖尿病肾病的发病过程。我们推测，抑制ER应激可通过抗氧化作用预防肾脏损伤。为了在体内和体外试验阻断ER应激是否能减轻氧化应激并改善糖尿病肾病，我们研究了ER应激抑制剂熊去氧胆酸（UDCA）对自发性糖尿病肾病db/db小鼠、ER应激诱导剂或高糖刺激的足细胞的影响。将小鼠分为3组（每组n = 6）：对照组（给予赋形剂）、db/db组（给予赋形剂）和UDCA组（db/db小鼠给予40 mg/kg/d UDCA）。治疗8周后，处死小鼠。采集血液和肾脏，用于评估白蛋白/肌酐比值、血尿素氮（BUN）、血清肌酐（SCr）、胰岛素、总胆固醇、甘油三酯、低密度脂蛋白胆固醇（LDL-C）、氧化型LDL-C、高密度脂蛋白胆固醇（HDL-C）、非酯化脂肪酸（NEFA）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、丙二醛（MDA）、SOD同工型和谷胱甘肽过氧化物酶1的表达，以及进行组织病理学检查。此外，用2'7'-二氯二氢荧光素二乙酸酯（DCFH-DA）荧光法检测活性氧（ROS）的生成。结果显示，UDCA在体内和体外均减轻了肾ER应激诱发的细胞死亡、氧化应激、肾功能障碍、ROS生成，上调了Bcl-2的表达并抑制了Bax的表达。因此，抑制ER应激可减轻氧化应激并发挥肾脏保护作用。
