Acute renal failure in zebrafish: a novel system to study a complex disease

被引:135
作者
Hentschel, DM
Park, KM
Cilenti, L
Zervos, AS
Drummond, I
Bonventre, JV
机构
[1] Harvard Univ, Inst Med, Brigham & Womens Hosp, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Div Renal, Dept Med, Boston, MA USA
[3] Massachusetts Gen Hosp, Renal Unit, Dept Med, Boston, MA USA
[4] Kyungpook Natl Univ, Sch Med, Dept Anat, Taejon, South Korea
[5] Univ Cent Florida, Biomol Sci Ctr, Dept Mol Biol & Microbiol, Orlando, FL USA
[6] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA USA
关键词
animal model; drug development; glomerular filtration; fluorescence;
D O I
10.1152/ajprenal.00386.2004
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Acute renal failure (ARF) is characterized by a very high mortality essentially unchanged over the past 40 years. Simple vertebrate models are needed to improve our understanding of ARF and facilitate the development of novel therapies for this clinical syndrome. Here, we demonstrate that gentamicin, a commonly used nephrotoxic antibiotic, causes larval zebrafish to develop ARF characterized by histological and functional changes that mirror aminoglycoside toxicity in higher vertebrates and inability of zebrafish to maintain fluid homeostasis. We developed a novel method to quantitate renal function in larval zebrafish and demonstrate a decline in glomerular filtration rate after gentamicin exposure. The antineoplastic drug cisplatin, whose use in humans is limited by kidney toxicity, also causes typical histological changes and a decline in renal function in larval zebrafish. A specific inhibitor of Omi/HtrA2, a serine protease implicated in cisplatin-induced apoptosis, prevented renal failure and increased survival. This protective effect was confirmed in a mouse model of cisplatin-induced nephrotoxicity. Therefore, zebrafish provides a unique model system, amenable to genetic manipulation and drug screening, to explore the pathophysiology of ARF and establish novel therapies with potential use in mammals.
引用
收藏
页码:F923 / F929
页数:7
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