Department of Marine Life Sciences and Fish Vaccine Research Center, Jeju National University, Jeju, Republic of Korea.
School of Applied Biosciences, Kyungpook National University, Daegu, Republic of Korea.
Am J Physiol Regul Integr Comp Physiol. 2020 May 1;318(5):R843-R854. doi: 10.1152/ajpregu.00130.2019. Epub 2020 Mar 18.
Cisplatin is a well-known chemotherapy medication used to treat numerous cancers. However, treatment with cisplatin in cancer therapy has major side effects, such as nephrotoxic acute kidney injury. Adult vertebrate kidneys are commonly used as models of cisplatin-induced nephrotoxic acute kidney injury. Embryonic zebrafish kidney is more simplified and is composed simply of two nephrons and thus is an excellent model for the investigation of cisplatin nephrotoxicity. Here, we developed a novel model to induce cisplatin nephrotoxicity in adult zebrafish and demonstrated that intraperitoneal injection of cisplatin caused a decline in kidney proximal tubular function based on fluorescein-labeled dextran uptake and alkaline phosphatase staining. We also showed that cisplatin induced histological injury of the kidney tubules, quantified by tubular injury scores on the periodic acid-Schiff-stained kidney sections. As shown in a mouse model of cisplatin-induced nephrotoxicity, the activation of poly(ADP-ribose) polymerase (PARP), an enzyme implicated in cisplatin-induced cell death, was markedly increased after cisplatin injection in adult zebrafish. Furthermore, pharmacological inhibition of PARP using a specific PARP inhibitor PJ 34 hydrochloride (PJ34) or 3-aminobenzamide ameliorated kidney proximal tubular functional and histological damages in cisplatin-injected adult zebrafish kidneys. Administration of a combination of PARP inhibitors PJ34 and 3-aminobenzamide additively protected renal function and histology in zebrafish and mouse models of cisplatin nephrotoxicity. In conclusion, these data suggest that adult zebrafish are not only suitable for drug screening and genetic manipulation but also useful as a simplified but powerful model to study the pathophysiology of cisplatin nephrotoxicity and establish new therapies for treating human kidney diseases.
顺铂是一种广为人知的化疗药物，用于治疗多种癌症。然而，顺铂在癌症治疗中的应用存在严重的副作用，如肾毒性急性肾损伤。成年脊椎动物肾脏通常被用作顺铂诱导的肾毒性急性肾损伤的模型。胚胎斑马鱼肾脏更为简化，仅由两个肾单位组成，因此是研究顺铂肾毒性的理想模型。在这里，我们开发了一种新的模型来诱导成年斑马鱼的顺铂肾毒性，并证明顺铂腹腔注射会导致肾脏近端肾小管功能下降，这可以通过荧光素标记的葡聚糖摄取和碱性磷酸酶染色来证实。我们还表明，顺铂诱导了肾脏小管的组织损伤，通过对过碘酸-希夫染色肾脏切片的肾小管损伤评分进行量化。在顺铂诱导的肾毒性的小鼠模型中，顺铂注射后，成年斑马鱼肾脏中多聚（ADP-核糖）聚合酶（PARP）的激活显著增加，PARP 是一种与顺铂诱导的细胞死亡有关的酶。此外，使用特异性 PARP 抑制剂 PJ 34 盐酸盐（PJ34）或 3-氨基苯甲酰胺抑制 PARP 的药理学作用可改善顺铂注射成年斑马鱼肾脏的近端肾小管功能和组织学损伤。PARP 抑制剂 PJ34 和 3-氨基苯甲酰胺的联合给药在斑马鱼和小鼠顺铂肾毒性模型中均能增强对肾功能和组织学的保护作用。总之，这些数据表明，成年斑马鱼不仅适合于药物筛选和遗传操作，而且还可以作为一种简化但强大的模型，用于研究顺铂肾毒性的病理生理学，并为治疗人类肾脏疾病建立新的治疗方法。
