Hentschel Dirk M, Park Kwon Moo, Cilenti Lucia, Zervos Antonis S, Drummond Iain, Bonventre Joseph V
Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Am J Physiol Renal Physiol. 2005 May;288(5):F923-9. doi: 10.1152/ajprenal.00386.2004. Epub 2004 Dec 29.
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.
急性肾衰竭（ARF）的特点是死亡率极高，在过去40年里基本没有变化。需要简单的脊椎动物模型来增进我们对ARF的理解，并促进针对这种临床综合征的新疗法的开发。在此，我们证明，常用的肾毒性抗生素庆大霉素会使斑马鱼幼体发生ARF，其组织学和功能变化反映了高等脊椎动物中的氨基糖苷类毒性，且斑马鱼无法维持液体稳态。我们开发了一种新方法来定量斑马鱼幼体的肾功能，并证明庆大霉素暴露后肾小球滤过率下降。抗肿瘤药物顺铂在人类中的使用受到肾毒性的限制，它也会导致斑马鱼幼体出现典型的组织学变化和肾功能下降。Omi/HtrA2是一种与顺铂诱导的细胞凋亡有关的丝氨酸蛋白酶，其特异性抑制剂可预防肾衰竭并提高存活率。这种保护作用在顺铂诱导的肾毒性小鼠模型中得到了证实。因此，斑马鱼提供了一个独特的模型系统，适用于基因操作和药物筛选，以探索ARF的病理生理学并建立可能在哺乳动物中使用的新疗法。
