Sharp Cierra N, Doll Mark A, Dupre Tess V, Shah Parag P, Subathra Marimuthu, Siow Deanna, Arteel Gavin E, Megyesi Judit, Beverly Levi J, Siskind Leah J
Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
Department of Medicine, University of Louisville, Louisville, Kentucky; James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; and.
Am J Physiol Renal Physiol. 2016 Mar 15;310(6):F560-8. doi: 10.1152/ajprenal.00512.2015. Epub 2016 Jan 6.
Cisplatin, a chemotherapeutic used for the treatment of solid cancers, has nephrotoxic side effects leading to acute kidney injury (AKI). Cisplatin cannot be given to patients that have comorbidities that predispose them to an increased risk for AKI. Even without these comorbidities, 30% of patients administered cisplatin will develop kidney injury, requiring the oncologist to withhold or reduce the next dose, leading to a less effective therapeutic regimen. Although recovery can occur after one episode of cisplatin-induced AKI, longitudinal studies have indicated that multiple episodes of AKI lead to the development of chronic kidney disease, an irreversible disease with no current treatment. The standard mouse model of cisplatin-induced AKI consists of one high dose of cisplatin (>20 mg/kg) that is lethal to the animal 3 days later. This model does not accurately reflect the dosing regimen patients receive nor does it allow for the long-term study of kidney function and biology. We have developed a repeated dosing model whereby cisplatin is given once a week for 4 wk. Comparison of the repeated dosing model with the standard dosing model demonstrated that inflammatory cytokines and chemokines were induced in the repeated dosing model, but levels of cell death were lower in the repeated dosing model. The repeated dosing model had increased levels of fibrotic markers (fibronectin, transforming growth factor-β, and α-smooth muscle actin) and interstitial fibrosis. These data indicate that the repeated dosing model can be used to study the AKI to chronic kidney disease progression as well as the mechanisms of this progression.
顺铂是一种用于治疗实体癌的化疗药物，具有肾毒性副作用，可导致急性肾损伤（AKI）。对于有合并症且易患AKI风险增加的患者，不能使用顺铂。即使没有这些合并症，接受顺铂治疗的患者中有30%会发生肾损伤，这就要求肿瘤学家停用或减少下一剂药物，从而导致治疗方案效果降低。虽然顺铂诱导的AKI发作一次后可以恢复，但纵向研究表明，多次AKI发作会导致慢性肾病的发展，这是一种目前无法治疗的不可逆疾病。顺铂诱导的AKI的标准小鼠模型是给予一次高剂量的顺铂（>20mg/kg），这会在3天后导致动物死亡。该模型不能准确反映患者接受的给药方案，也不允许对肾功能和生物学进行长期研究。我们开发了一种重复给药模型，即每周给予顺铂一次，共4周。将重复给药模型与标准给药模型进行比较表明，重复给药模型中诱导了炎性细胞因子和趋化因子，但重复给药模型中的细胞死亡水平较低。重复给药模型中纤维化标志物（纤连蛋白、转化生长因子-β和α-平滑肌肌动蛋白）水平升高且出现间质纤维化。这些数据表明，重复给药模型可用于研究AKI向慢性肾病的进展以及这种进展的机制。
