Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
FASEB J. 2021 Jun;35(6):e21661. doi: 10.1096/fj.202100174R.
Acute kidney injury (AKI) is commonly encountered and causes high mortality in hospitalized patients; however, effective therapies for AKI have still not been established. Accordingly, we performed a rodent model with acute renal ischemia-reperfusion (IR) and tested the hypothesis that combined tacrolimus and melatonin therapy could be superior to either one for protecting the kidney against IR injury. Adult-male SD rat (n = 30) were equally categorized into group 1 (receiving laparotomy only), group 2 (IR treated by 3.0 cc/normal-saline), group 3 [IR + tacrolimus/0.5 mg/kg by intravenous administration at 30 minutes and at days 1/2/3 after IR], group 4 (IR + melatonin/50 mg/kg by intra-peritoneal administration at 30 minutes and 25 mg/kg at days 1/2/3 after IR] and group 5 (IR + tacrolimus +melatonin). By day 3 after IR, the creatinine/BUN levels and ratio of urine protein to urine creatinine were highest in group 2, lowest in group 1 and significantly lower in group 5 than in groups 3/4 (all P < .0001), but they did not differ between the groups 3/4. The protein expressions of oxidative-stress (p47phox/NOX-1/NOX-2/NOX-4), upstream (TLR4/MAL/MyD88/TRAF6/ASK1/MKK4/MKK7/NF-κB) and downstream (IL-6/INF-γ/MMP-9/IL-1ß) inflammatory signaling, MAPK-family-signaling cascades(ERK1/2, JNK/p38/c-JUN), apoptotic/autophagic (p53/caspase 3/mitochondrial-Bax, ratio of LC3B-II/LC3B-I), and mitochondrial-damaged (cyclophilin D/cytochrome C/DRP1) biomarkers, and the expressions of inflammatory-immune cells (F4/80, CD14/CD3/CD8) as well as the kidney injured score exhibited an identical pattern of creatinine level (all P < .0001). In conclusion, combined tacrolimus and melatonin therapy was better than either single one on protecting the kidney functional and anatomical integrity against IR injury through suppressing inflammation and the generation of oxidative stress.
急性肾损伤（AKI）在住院患者中很常见，死亡率很高；然而，AKI 的有效治疗方法仍未建立。因此，我们进行了一项伴有急性肾缺血再灌注（IR）的啮齿动物模型研究，并检验了以下假说，即联合使用他克莫司和褪黑素治疗可能优于单独使用一种药物来保护肾脏免受 IR 损伤。30 只成年雄性 SD 大鼠（n=30）平均分为 5 组：第 1 组（仅接受剖腹术）、第 2 组（IR 处理，用 3.0cc/生理盐水）、第 3 组[IR+他克莫司/0.5mg/kg 静脉注射，于 IR 后 30 分钟和第 1/2/3 天]、第 4 组（IR+褪黑素/50mg/kg 腹腔注射，于 IR 后 30 分钟和第 1/2/3 天 25mg/kg）和第 5 组（IR+他克莫司+褪黑素）。IR 后第 3 天，第 2 组肌酐/尿素氮水平和尿蛋白/尿肌酐比值最高，第 1 组最低，第 5 组明显低于第 3 组和第 4 组（均 P<0.0001），但第 3 组和第 4 组之间无差异。氧化应激（p47phox/NOX-1/NOX-2/NOX-4）、上游（TLR4/MAL/MyD88/TRAF6/ASK1/MKK4/MKK7/NF-κB）和下游（IL-6/INF-γ/MMP-9/IL-1β）炎症信号、MAPK 家族信号级联（ERK1/2、JNK/p38/c-JUN）、凋亡/自噬（p53/caspase 3/线粒体-Bax、LC3B-II/LC3B-I 比值）和线粒体损伤（环孢素 D/细胞色素 C/DRP1）生物标志物以及炎症免疫细胞（F4/80、CD14/CD3/CD8）的表达和肾脏损伤评分的变化与肌酐水平的变化模式相同（均 P<0.0001）。综上所述，联合使用他克莫司和褪黑素治疗在保护肾脏功能和解剖完整性方面优于单独使用一种药物，可通过抑制炎症和氧化应激的产生。
