Shen Xiaohua, Hu Bo, Xu Guangtao, Chen Fengjuan, Ma Ruifen, Zhang Nenghua, Liu Jie, Ma Xiaoqin, Zhu Jia, Wu Yuhong, Shen Ruilin
Department of Chemical Pathology, Urinary Surgery, Nephrology, Gynecology and Intensive Care Unit, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing University Affiliated TCM Hospital, Jiaxing, China.
Diabetes Institute, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, China.
Kidney Blood Press Res. 2017;42(2):369-378. doi: 10.1159/000477947. Epub 2017 Jun 15.
BACKGROUND/AIMS: Diabetes mellitus can exacerbate renal ischemia-reperfusion (I/R) injury (RI/RI). The aim of the present study was to evaluate the protective effect of GSK-3β inhibition (TDZD-8) on I/R-induced renal injury through the Nrf2/HO-1 pathway in a streptozocin (STZ)-induced diabetic rat model.
STZ-induced diabetic rats preconditioned with TDZD-8 and ZnPP were subjected to renal I/R. The extent of renal morphologic lesions. Renal function was assessed from blood urea nitrogen (BUN) and serum creatinine (Scr), as determined utlizing commercial kits. Oxidative stress and inflammatory activity in the kidney tissue was estimated from levels of malondialdehyde (MDA), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), as well as the activities of superoxide dismutase (SOD) and glutathione (GSH) using qRT-PCR and ELISA. The expressions of Nrf2, HO-1, Bcl-2 and NF-κB in the renal tissue were measured by qRT-PCR and western blotting.
I/R-induced renal inflammation was reduced significantly by TDZD-8 pretreatment. Preconditioning with TDZD-8 suppressed NF-κB expression and enhanced Bcl-2 expression in the renal tissue. The upregulated level of malondialdehyde (MDA), and reduced activities of superoxide dismutase (SOD) and glutathione (GSH) in I/R-shocked rats were markedly restored by TDZD-8 pretreatment. Furthermore, pretreatment with TDZD-8 enhanced activation of the Nrf2/HO-1 pathway in the renal tissue of diabetic RI/RI rats.
These findings suggest that preconditioning with TDZD-8 may protect the kidney from I/R-induced damage via the activation of the Nrf2/HO-1 pathway in STZ-induced diabetic rats. Further detailed studies are needed to further clarify the underlying mechanisms.
背景/目的：糖尿病可加重肾缺血再灌注（I/R）损伤（RI/RI）。本研究旨在评估在链脲佐菌素（STZ）诱导的糖尿病大鼠模型中，抑制糖原合成酶激酶-3β（GSK-3β，TDZD-8）通过Nrf2/HO-1途径对I/R诱导的肾损伤的保护作用。
用TDZD-8和锌原卟啉（ZnPP）预处理STZ诱导的糖尿病大鼠，使其遭受肾I/R。评估肾脏形态学损伤程度。使用商用试剂盒通过测定血尿素氮（BUN）和血清肌酐（Scr）来评估肾功能。通过实时定量聚合酶链反应（qRT-PCR）和酶联免疫吸附测定（ELISA），根据丙二醛（MDA）、白细胞介素-10（IL-10）、肿瘤坏死因子-α（TNF-α）和一氧化氮（NO）水平以及超氧化物歧化酶（SOD）和谷胱甘肽（GSH）活性来估计肾组织中的氧化应激和炎症活性。通过qRT-PCR和蛋白质免疫印迹法测量肾组织中Nrf2、HO-1、Bcl-2和核因子-κB（NF-κB）的表达。
TDZD-8预处理显著减轻了I/R诱导的肾炎症。TDZD-8预处理抑制了肾组织中NF-κB的表达并增强了Bcl-2的表达。TDZD-8预处理显著恢复了I/R损伤大鼠中丙二醛（MDA）上调水平以及超氧化物歧化酶（SOD）和谷胱甘肽（GSH）活性的降低。此外，TDZD-8预处理增强了糖尿病RI/RI大鼠肾组织中Nrf2/HO-1途径的激活。
这些发现表明，在STZ诱导的糖尿病大鼠中，TDZD-8预处理可能通过激活Nrf2/HO-1途径保护肾脏免受I/R诱导的损伤。需要进一步详细研究以进一步阐明其潜在机制。
