Department of Pharmacology and Toxicology, University of Louisville , Louisville, Kentucky.
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System , Little Rock, Arkansas.
Am J Physiol Renal Physiol. 2018 Jul 1;315(1):F161-F172. doi: 10.1152/ajprenal.00636.2017. Epub 2018 Jan 31.
Cisplatin is used to treat many solid cancers, but its dose-limiting side effect is nephrotoxicity, causing acute kidney injury in 30% of patients. Previously, we have developed a mouse model that better recapitulates the cisplatin dosing regimen humans receive and found that repeated dosing of cisplatin induces interstitial renal fibrosis. Chronic kidney disease is progressive and is characterized by chronic inflammation, worsening interstitial fibrosis, development of glomerulosclerosis, and endothelial dysfunction. To determine if damage caused by repeated cisplatin dosing results in bona fide chronic kidney disease, mice were treated with our repeated dosing regimen and then aged for 6 mo. These mice had progressive, chronic inflammation and worsened interstitial fibrosis compared with mice euthanized after day 24. Mice aged for 6 mo developed glomerular pathologies, and endothelial dysfunction was persistent. Mice treated with only two doses of cisplatin had little inflammation or kidney damage. Thus repeated dosing of cisplatin causes long-term effects that are characteristic of chronic kidney disease. This translational mouse model of cisplatin injury may better represent the 70% of patients that do not develop clinical acute kidney injury and can be used to identify both biomarkers for early injury, as well as novel therapeutic targets for the prevention of cisplatin-induced chronic kidney disease.
顺铂用于治疗多种实体瘤,但它的剂量限制副作用是肾毒性,导致 30%的患者发生急性肾损伤。此前,我们已经开发了一种小鼠模型,该模型更好地模拟了人类接受的顺铂给药方案,并且发现重复给予顺铂会引起间质肾纤维化。慢性肾脏病是进行性的,其特征为慢性炎症、间质纤维化恶化、肾小球硬化和内皮功能障碍。为了确定重复顺铂给药引起的损伤是否导致真正的慢性肾脏病,我们用我们的重复给药方案治疗小鼠,然后让其老化 6 个月。与第 24 天安乐死的小鼠相比,这些小鼠出现了进行性、慢性炎症和间质纤维化恶化。经过 6 个月老化的小鼠出现了肾小球病变,内皮功能障碍持续存在。仅接受两剂顺铂治疗的小鼠炎症或肾脏损伤很小。因此,重复给予顺铂会产生慢性肾脏病的特征性长期影响。这种顺铂损伤的转化小鼠模型可能更好地代表了 70%未发生临床急性肾损伤的患者,可用于鉴定早期损伤的生物标志物,以及预防顺铂引起的慢性肾脏病的新治疗靶点。