Cisplatin nephrotoxicity is induced via poly(ADP-ribose) polymerase activation in adult zebrafish and mice

被引:15
作者
Kim, Myoung-Jin [1 ,2 ,3 ]
Moon, Daeun [4 ]
Jung, Sumi [1 ,2 ]
Lee, Jehee [1 ,2 ]
Kim, Jinu [4 ,5 ]
机构
[1] Jeju Natl Univ, Dept Marine Life Sci, Jeju, South Korea
[2] Jeju Natl Univ, Fish Vaccine Res Ctr, Jeju, South Korea
[3] Kyungpook Natl Univ, Sch Appl Biosci, Daegu, South Korea
[4] Jeju Natl Univ, Interdisciplinary Grad Program Adv Convergence Te, Jeju, South Korea
[5] Jeju Natl Univ, Dept Anat, Sch Med, Jeju, Self Governing, South Korea
基金
新加坡国家研究基金会;
关键词
cisplatin; PARP; proximal tubule; toxicity; zebrafish; NECROTIC CELL-DEATH; ACUTE-RENAL-FAILURE; REPERFUSION INJURY; KIDNEY INJURY; STEM-CELLS; MECHANISMS; SPERMIDINE; ISCHEMIA; NECROSIS;
D O I
10.1152/ajpregu.00130.2019
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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.
引用
收藏
页码:R843 / R854
页数:12
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