Sung Pei-Hsun, Chiang Hsin-Ju, Wallace Christopher Glenn, Yang Chih-Chao, Chen Yen-Ta, Chen Kuan-Hung, Chen Chih-Hung, Shao Pei-Lin, Chen Yung-Lung, Chua Sarah, Chai Han-Tan, Chen Yi-Ling, Huang Tien-Hung, Yip Hon-Kan, Lee Mel S
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan, R.O.C.
Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan, R.O.C.
Am J Transl Res. 2017 Jul 15;9(7):3167-3183. eCollection 2017.
This study tested the hypothesis that combined therapy with exendin-4 (Ex4) and autologous adipose-derived mesenchymal stem cells (ADMSCs) was superior to either alone for protecting renal function against acute kidney ischemia-reperfusion (IR; 40-min ischemia/27-h reperfusion) injury when complicated by sepsis syndrome (SS; by cecal-ligation-puncture). Adult-male Sprague-Dawley rats (n=40) were equally divided into group 1 (sham-control), group 2 (IR-SS), group 3 (IR-SS + Ex4, 10 μg/kg subcutaneously 30 min after reperfusion and daily for 3 days), group 4 [IR-SS + ADMSC (1.2 × 10)], and group 5 (IR-SS + Ex4 + ADMSC). The circulating levels of BUN and creatinine and the ratio of urine protein to creatinine were highest in group 2, lowest in group 1, significantly higher in groups 3 and 4 than group 5, and significantly higher in group 3 than in group 4 (all P<0.0001). Microscopic findings of kidney injury score, inflammatory cells (CD14+, F4/80+), and expressions of glomerular-damage indicators (FSP-1+/WT-1+) and renal tubular-damage indicators (KIM-1+/snail+) showed an identical pattern, whereas expressions of indices of glomerular-integrity (ZO-1+/p-cadherin+/podocin+/synaptopodin+) and angiogenesis (CD31+/vWF+/number of small vessels) biomarkers demonstrated an opposite pattern, to that of creatinine level (all P<0.001). Protein expressions of inflammatory (MMP-9/IL-1ß/TNF-α/TLR-2/TLR-4), apoptotic (cleaved caspase-3/PARP/mitochondrial Bax), and oxidative-stress (NOX-1/NOX-2/oxidized protein) biomarkers exhibited an identical pattern, whereas anti-inflammatory (IL-10/IL-4) biomarkers displayed an opposite pattern, to that of creatinine level (all P<0.001). In conclusion, combined Ex4 and ADMSC therapy significantly protected kidney from acute IR-SS injury.
当合并脓毒症综合征（SS；通过盲肠结扎穿刺诱导）时，艾塞那肽-4（Ex4）与自体脂肪间充质干细胞（ADMSC）联合治疗在保护肾功能免受急性肾缺血再灌注（IR；40分钟缺血/27小时再灌注）损伤方面优于单独使用Ex4或ADMSC。成年雄性Sprague-Dawley大鼠（n = 40）被平均分为1组（假手术对照）、2组（IR-SS）、3组（IR-SS + Ex4，再灌注后30分钟皮下注射10μg/kg，每日1次，共3天）、4组[IR-SS + ADMSC（1.2×10）]和5组（IR-SS + Ex4 + ADMSC）。2组血尿素氮和肌酐的循环水平以及尿蛋白与肌酐的比值最高，1组最低，3组和4组显著高于5组，且3组显著高于4组（均P<0.0001）。肾损伤评分、炎性细胞（CD14+、F4/80+）的微观检查结果，以及肾小球损伤指标（FSP-1+/WT-1+）和肾小管损伤指标（KIM-1+/蜗牛蛋白+）的表达呈现相同模式，而肾小球完整性指标（ZO-1+/p-钙黏蛋白+/足突蛋白+/突触素蛋白+）和血管生成（CD31+/血管性血友病因子+/小血管数量）生物标志物的表达呈现与肌酐水平相反的模式（均P<0.001）。炎性（基质金属蛋白酶-9/白细胞介素-1β/肿瘤坏死因子-α/Toll样受体-2/Toll样受体-4）、凋亡（裂解的半胱天冬酶-3/聚（ADP-核糖）聚合酶/线粒体Bax）和氧化应激（NADPH氧化酶-1/NADPH氧化酶-2/氧化蛋白）生物标志物的蛋白表达呈现相同模式，而抗炎（白细胞介素-10/白细胞介素-4）生物标志物的表达呈现与肌酐水平相反的模式（均P<0.001）。总之，Ex4与ADMSC联合治疗能显著保护肾脏免受急性IR-SS损伤。
