Heme Oxygenase-1 counteracts contrast-induced acute kidney injury in diabetic rats via antioxidant pathway

Contrast-induced acute kidney injury (CI-AKI) is the third leading cause of hospital-acquired kidney injury. Diabetes Mellitus is an important risk factor for contrast-induced acute kidney injury and its identification is predictable. Heme oxygenase-1 (HO-1) is a new therapeutic target that exerts antioxidant effect against kidney diseases. This study investigated the effect of HO-1 on metabolic functions, oxidative profile and morphology at CI-AKI in the presence of Diabetes Mellitus. Twenty-eight male Wistar rats weighing 250-300g were randomized into four groups: C (control)- rats submitted to left uninephrectomy on the 1th day; DM- Diabetes was induced by a single dose of intravenous streptozotocin-65mg/kg on the 20th day; DMIC- iodinated contrast- meglumine ioxithalamate (6ml/kg, intraperitoneal, once) rats and DMICH- hemin (HO-1 inducer; 10mg/kg; intraperitoneal; 60 minutes before iodinated contrast) were infused on the 85th day. Diabetic groups showed polyphagia, polydipsia, polyuria, and increase in the blood glucose and in the kidney/animal weight ratio. Iodinated contrast reduced the creatinine clearance and thiols in renal tissue with a prominent increase in urinary NGAL, peroxides, oxide nitric and thiobarbituric acid-reactive substances (TBARS), these parameters were significantly changed by HO-1 inducer. Kidney histology showed tubular cells vacuolization and edema in iodinated contrast animals. The data highlight the HO-1 protective effect against contrast-induced AKI associated with chronic disease, DM.

造影剂诱导的急性肾损伤（Contrast-induced acute kidney injury, CI-AKI）是医院获得性肾损伤的第三大病因。糖尿病（Diabetes Mellitus）是造影剂诱导的急性肾损伤的重要危险因素，其临床识别具有可预测性。血红素氧合酶-1（Heme oxygenase-1, HO-1）是一种新型治疗靶点，可通过发挥抗氧化作用缓解肾脏疾病损伤。本研究旨在探讨糖尿病状态下，血红素氧合酶-1对造影剂诱导急性肾损伤大鼠的代谢功能、氧化应激特征及肾脏形态学的影响。本研究将28只体重250~300g的雄性Wistar大鼠随机分为4组：C组（对照组）：于造模第1日行左侧单肾切除术；DM组：于第20日经静脉单次注射65mg/kg链脲佐菌素以诱导糖尿病模型；DMIC组：于第85日经腹腔单次给予6ml/kg碘造影剂碘沙葡胺（meglumine ioxithalamate）；DMICH组：于碘造影剂给药前60分钟经腹腔注射10mg/kg血红素（HO-1诱导剂），随后给予碘造影剂处理。结果显示，糖尿病组大鼠均出现多食、多饮、多尿症状，血糖水平及肾脏/体质量比值均显著升高。碘造影剂给药可降低大鼠肌酐清除率及肾组织巯基含量，同时显著升高尿中性粒细胞明胶酶相关脂质运载蛋白（Neutrophil Gelatinase-Associated Lipocalin, NGAL）、过氧化物、一氧化氮及硫代巴比妥酸反应物（thiobarbituric acid-reactive substances, TBARS）水平；上述异常指标的变化可被HO-1诱导剂显著改善。肾脏组织病理学检查显示，碘造影剂处理组大鼠肾小管上皮细胞出现空泡变性及间质水肿。本研究数据证实，血红素氧合酶-1对合并慢性糖尿病的造影剂诱导急性肾损伤具有明确的保护作用。