Zhao Kailiang, Chen Chen, Shi Qiao, Deng Wenhong, Zuo Teng, He Xiaobo, Liu Tianyi, Zhao Liang, Wang Weixing
Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Mol Med Rep. 2014 Dec;10(6):3185-92. doi: 10.3892/mmr.2014.2650. Epub 2014 Oct 15.
The aim of the present study was to investigate the efficacy of 4‑benzyl‑2‑methyl‑1,2,4‑thiadiazolidine‑3,5‑dione (TDZD‑8), the selective inhibitor of glycogen synthase kinase‑3β (GSK‑3β), on the development of acute kidney injury in an experimental model of sodium taurocholate‑induced severe acute pancreatitis (SAP) in rats. The serum amylase, lipase, interleukin‑1β and interleukin‑6 levels, and the pancreatic pathological score were examined to determine the magnitude of pancreatitis injury. The serum creatinine and blood urea nitrogen levels, myeloperoxidase (MPO) activity and renal histological grading were measured to assess the magnitude of SAP‑induced acute kidney injury. The activation of nuclear factor‑κB (NF‑κB) was examined using an immunohistochemistry assay. The expression of GSK‑3β, phospho‑GSK‑3β (Ser9), tumour necrosis factor‑α (TNF‑α), intercellular adhesion molecule‑1 (ICAM‑1) and inducible nitric oxide synthase (iNOS) protein in the kidney was characterised using western blot analysis. TDZD‑8 attenuated (i) serum amylase, lipase and renal dysfunction; (ii) the serum concentrations of proinflammatory cytokines; (iii) pancreatic and renal pathological injury; (iv) renal MPO activity and (v) NF‑κB activation and TNF‑α, ICAM‑1 and iNOS protein expression in the kidney. The results obtained in the present study suggest that the inhibition of GSK‑3β attenuates renal disorders associated with SAP through the inhibition of NF‑κB activation and the downregulation of the expression of proinflammatory cytokines, TNF‑α, ICAM‑1 and iNOS in rats. Blocking GSK‑3β protein kinase activity may be a novel approach to the treatment of this inflammatory condition.
本研究的目的是在牛磺胆酸钠诱导的大鼠重症急性胰腺炎（SAP）实验模型中，研究糖原合酶激酶-3β（GSK-3β）的选择性抑制剂4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮（TDZD-8）对急性肾损伤发展的影响。检测血清淀粉酶、脂肪酶、白细胞介素-1β和白细胞介素-6水平以及胰腺病理评分，以确定胰腺炎损伤的程度。测量血清肌酐和血尿素氮水平、髓过氧化物酶（MPO）活性和肾脏组织学分级，以评估SAP诱导的急性肾损伤的程度。采用免疫组织化学分析法检测核因子-κB（NF-κB）的激活情况。使用蛋白质印迹分析对肾脏中GSK-3β、磷酸化GSK-3β（Ser9）、肿瘤坏死因子-α（TNF-α）、细胞间黏附分子-1（ICAM-1）和诱导型一氧化氮合酶（iNOS）蛋白的表达进行表征。TDZD-8减轻了：（i）血清淀粉酶、脂肪酶和肾功能障碍；（ii）促炎细胞因子的血清浓度；（iii）胰腺和肾脏病理损伤；（iv）肾脏MPO活性；以及（v）肾脏中NF-κB激活和TNF-α、ICAM-1和iNOS蛋白表达。本研究获得的结果表明，抑制GSK-3β可通过抑制NF-κB激活以及下调大鼠促炎细胞因子TNF-α、ICAM-1和iNOS的表达来减轻与SAP相关的肾脏疾病。阻断GSK-3β蛋白激酶活性可能是治疗这种炎症性疾病的一种新方法。
