Abstract
Genetic disorders account for a wide range of renal diseases emerging during childhood and adolescence. Due to the utilization of modern biochemical and biomedical techniques, the number of identified disease-associated genes is increasing rapidly. Modeling of congenital human disease in animals is key to our understanding of the biological mechanism underlying pathological processes and thus developing novel potential treatment options. The zebrafish (Danio rerio) has been established as a versatile small vertebrate organism that is widely used for studying human inherited diseases. Genetic accessibility in combination with elegant experimental methods in zebrafish permit modeling of human genetic diseases and dissecting the perturbation of underlying cellular networks and physiological processes. Beyond its utility for genetic analysis and pathophysiological and mechanistic studies, zebrafish embryos, and larvae are amenable for phenotypic screening approaches employing high-content and high-throughput experiments using automated microscopy. This includes large-scale chemical screening experiments using genetic models for searching for disease-modulating compounds. Phenotype-based approaches of drug discovery have been successfully performed in diverse zebrafish-based screening applications with various phenotypic readouts. As a result, these can lead to the identification of candidate substances that are further examined in preclinical and clinical trials. In this review, we discuss zebrafish models for inherited kidney disease as well as requirements and considerations for the technical realization of drug screening experiments in zebrafish.
Highlights
Modern genetic diagnostics allow the rapid discovery of human disease-associated mutations
Zebrafish models can recapitulate human genetic glomerulopathies, i.e., a variety of podocytopathies that clinically often manifest by steroid-resistant nephrotic syndrome (SRNS) due to podocyte foot process effacement
Whereas in many studies of genetic glomerulopathies the zebrafish has been used to model human disease-associated phenotypes, disruption of the glomerular filtration barrier can only be visualized by ultrastructural techniques like superresolution or electron microscopy that are not compatible with large-scale chemical screens
Summary
Reviewed by: Ruxandra Bachmann-Gagescu, Universität Zürich, Switzerland Rachel Lennon, University of Manchester, United Kingdom. Beyond its utility for genetic analysis and pathophysiological and mechanistic studies, zebrafish embryos, and larvae are amenable for phenotypic screening approaches employing high-content and high-throughput experiments using automated microscopy. This includes large-scale chemical screening experiments using genetic models for searching for disease-modulating compounds. Phenotype-based approaches of drug discovery have been successfully performed in diverse zebrafish-based screening applications with various phenotypic readouts. As a result, these can lead to the identification of candidate substances that are further examined in preclinical and clinical trials.
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