ZEBRAFISH: A NOVEL SYSTEM TO STUDY KIDNEY DISEASE

Abstract

Acute renal failure is a serious disease with high mortality rates that have not dropped over the past 40 years. This lack of advancement reflects the struggle to find a suitable model system to study the disease; current mammalian models used to study acute renal failure have proved to be inadequate for a number of reasons. Surprisingly, zebrafish offer many advantages over the typical rat or mouse model. Early larval zebrafish kidneys possess the biological complexity inherent to kidneys of higher vertebrates. Unlike their mammalian counterparts, zebrafish are translucent, facilitating microscopic observation along the entire length of their kidneys. Zebrafish tolerate manipulation on a molecular level, and their large numbers of offspring make them an important tool for drug discovery and the generation of transgenic fish. Thus, zebrafish might be a good model system to study acute renal failure. That is...if zebrafish can suffer from it in the first place.To find out whether zebrafish can develop acute renal failure, Hentschel,Bonventre and their team injected zebrafish embryos with the antibiotic gentamicin and the cancer therapeutic cisplatin, which are known to cause kidney damage in humans. But would they have the same effect in zebrafish?Sure enough, when the team analysed the kidney tissue of the treated zebrafish embryos, they saw morphological changes that are consistent with acute renal failure. Zebrafish embryos treated with gentamicin or cisplatin also suffered from severe swelling in a time- and dose-dependent manner, reflecting an inability to regulate water, probably due to the loss of glomerular function.To assess this potential kidney damage, the team measured glomerular filtration rate in the treated zebrafish embryos. This can be estimated by determining the excretion of a substance that is only filtered at the kidney's glomeruli and not significantly secreted or reabsorbed by its tubules. Thus,they injected dextran or inulin, two substances that are filtered by the glomeruli but are neither secreted nor reabsorbed by kidney tubules, into zebrafish bloodstreams. They had labelled both substances with a fluorescent dye. To determine whether the kidneys were successfully filtering and excreting the fluorescently labelled substances, the team monitored the decline in fluorescence intensity over time. They measured fluorescence intensity in zebrafish hearts by taking fluorescent microscopy images of individual fish immediately after dextran or inulin injection and 1, 5 and 24 h later. They found that the rate of decline in fluorescence intensity was greatly reduced in gentamicin-injected fish, indicating that their damaged kidneys were not excreting the substances. The team observed a 75% and 67%reduction in dextran and inulin excretion, respectively. They went on to investigate whether treatments used successfully in mammals with gentamicin-and cisplatin-induced kidney damage would also be effective in zebrafish. They found that, like in mammals, the amino acid taurine prevents gentamicin-induced damage and the compound Ucf-101 prevents the effects of cisplatin in zebrafish.And so, the old August Krogh/Claude Bernard adage that there is a perfect animal system for every biological problem comes to mind in this case. Gentamicin- or cisplatin-injected larval zebrafish develop renal failure with characteristics typical of those in higher vertebrates and respond to treatments in the same manner as higher vertebrates. This finding consolidates their role as valuable and unique models for studying the pathophysiology of acute renal failure and for establishing novel therapies for use in humans. Who knew?