Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions.

多项研究证据表明，α1-抗胰蛋白酶（alpha-1-antitrypsin, AAT）——血清中主要的丝氨酸蛋白酶抑制剂——具有抗炎与细胞保护作用。本研究旨在探究人源α1-抗胰蛋白酶（human AAT, hAAT）单药治疗在缺血诱导的急性肾损伤早期及恢复阶段的作用效果。本研究通过对雄性C57Bl/6小鼠双侧肾动脉与静脉夹闭20分钟，构建轻度肾缺血再灌注（ischemia-reperfusion, I/R）损伤模型。于术前1天至术后7天每日腹腔注射（intraperitoneally, i.p.）80 mg/kg的hAAT（商品名Prolastin®）；对照组小鼠则注射等量的人血清白蛋白（human serum albumin, hAlb）。分别于再灌注后2小时、1天、2天、3天、8天及15天采集血浆、尿液与肾脏组织，用于组织学与生化分析。在双侧肾I/R损伤造模后，hAAT可部分维持肾功能与肾小管完整性，同时伴随肾脏巨噬细胞浸润减少，以及尿液与血浆中中性粒细胞明胶酶相关脂质运载蛋白（neutrophil gelatinase-associated lipocalin, NGAL）蛋白水平显著降低。在恢复阶段，hAAT可显著降低尿液中肾损伤分子1（kidney injury molecule-1, KIM-1）的蛋白水平，但对肾纤维化无明显影响。尽管本研究中hAAT给药的效应量有限，因此需谨慎评估本研究结果的临床相关性，但上述数据仍支持这种天然蛋白可改善缺血性与炎症性疾病状态的潜在应用价值。