Lung cancer-kidney cross talk induces kidney injury, interstitial fibrosis, and enhances cisplatin-induced nephrotoxicity.
Lung cancer-kidney cross talk induces kidney injury, interstitial fibrosis, and enhances cisplatin-induced nephrotoxicity.
复制标题
肺癌-肾交互作用会诱发肾损伤、间质纤维化，并增强顺铂引起的肾毒性。
DOI：
10.1152/ajprenal.00317.2022
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Siskind,LeahJ
中科院分区：
文献类型：
--
作者：
Orwick,Andrew;Sears,SophiaM;Sharp,CierraN;Doll,MarkA;Shah,ParagP;Beverly,LeviJ;Siskind,LeahJ
癌症患者代表了一个独特的患者群体，他们对肾脏疾病的易感性增加。药物所致的急性肾损伤(AKI)是癌症患者的常见问题。顺铂是一种用于许多实体器官癌症的高效治疗方法，在30%的患者中会导致AKI，增加了慢性肾脏疾病发展的风险。大多数临床前顺铂毒性研究已经在没有癌症的小鼠身上完成。我们认为，癌症患者的生理学在临床前模型中没有得到充分的反映，本研究的目的是确定肺癌将如何改变顺铂的肾毒性。使用了肺癌的基因工程小鼠模型和同基因异种移植模型。将小鼠分为以下四组：1)非癌症/载药组，2)非癌症/顺铂组，3)癌症/载药组，4)癌症/顺铂组。顺铂腹腔注射，每周1次，连续4wk。动物在最后一次顺铂注射后72小时被安乐死。反复使用低剂量顺铂后，肺癌小鼠的肾脏毒性、损伤和纤维化增加。此外，在顺铂治疗之前，肺癌本身就会导致肾脏损伤和肾脏纤维化。总之，这是我们所知道的第一项评估癌症对肾脏的影响与顺铂的肾毒性相结合的研究。我们认为，癌症是对肾脏的第一次打击，反复服用顺铂造成的后续损害变得无法治愈，导致AKI和进展为慢性肾脏疾病。NEW&NOTEWORTHY癌症患者肾功能受损，对肾毒性药物的敏感性增加。顺铂是一种常用的化疗药物，其剂量限制副作用为肾毒性。顺铂的肾毒性几乎只在没有癌症的小鼠身上进行研究。我们目前的临床前模型不能充分代表癌症患者的复杂性。这项研究表明，肺癌小鼠的肾脏毒性、损伤和纤维化增加，顺铂治疗会加剧这种情况。这些结果强调了使用临床前模型的必要性，这些模型可以更准确地捕捉接受顺铂治疗的癌症患者的生理变化。
Patients with cancer represent a unique patient population with increased susceptibility to kidney disease. Drug-induced acute kidney injury (AKI) in patients with cancer is a common problem. Cisplatin is a highly effective treatment used in many solid-organ cancers and causes AKI in 30% of patients, increasing the risk of chronic kidney disease development. Most preclinical cisplatin toxicity studies have been completed in mice without cancer. We believe that the physiology of patients with cancer is not adequately represented in preclinical models, and the objective of this study was to determine how lung cancer will alter the nephrotoxicity of cisplatin. A genetically engineered mouse model and a syngeneic xenograft model of lung cancer were used. Mice were divided into the following four groups:1) noncancer/vehicle,2) noncancer/cisplatin,3) cancer/vehicle, and4) cancer/cisplatin. Mice were administered cisplatin via intraperitoneal injection once a week for 4 wk. Animals were euthanized 72 h following their final cisplatin injection. Mice with lung cancer had increased renal toxicity, injury, and fibrosis following repeated low doses of cisplatin. In addition, lung cancer alone induced kidney injury and fibrosis in the kidney before cisplatin treatment. In conclusion, this is the first study that we are aware of that assesses the impact of cancer on the kidney in conjunction with the nephrotoxicity of cisplatin. We believe that cancer is providing the first hit to the kidney and the subsequent damage from repeated doses of cisplatin becomes unsurmountable, leading to AKI and progression to chronic kidney disease.NEW & NOTEWORTHYPatients with cancer have impaired kidney function and increased susceptibility to nephrotoxic agents. Cisplatin is a commonly used chemotherapeutic with nephrotoxicity as the dose-limiting side effect. Cisplatin nephrotoxicity is almost exclusively studied in mice without cancer. Our current preclinical models do not adequately represent the complexity of patients with cancer. This study demonstrates increased renal toxicity, injury, and fibrosis in mice with lung cancer, which is exacerbated with cisplatin treatment. These results highlight the necessity of using preclinical models that more accurately capture the altered physiology of patients with cancer treated with cisplatin.