Ion transport in the zebrafish kidney from a human disease angle: possibilities, considerations, and future perspectives

Abstract

Unique experimental advantages, such as its embryonic/larval transparency, high-throughput nature, and ease of genetic modification, underpin the rapid emergence of the zebrafish (Danio rerio) as a preeminent model in biomedical research. Particularly in the field of nephrology, the zebrafish provides a promising model for studying the physiological implications of human solute transport processes along consecutive nephron segments. However, although the zebrafish might be considered a valuable model for numerous renal ion transport diseases and functional studies of many channels and transporters, not all human renal electrolyte transport mechanisms and human diseases can be modeled in the zebrafish. With this review, we explore the ontogeny of zebrafish renal ion transport, its nephron structure and function, and thereby demonstrate the clinical translational value of this model. By critical assessment of genomic and amino acid conservation of human proteins involved in renal ion handling (channels, transporters, and claudins), kidney and nephron segment conservation, and renal electrolyte transport physiology in the zebrafish, we provide researchers and nephrologists with an indication of the possibilities and considerations of the zebrafish as a model for human renal ion transport. Combined with advanced techniques envisioned for the future, implementation of the zebrafish might expand beyond unraveling pathophysiological mechanisms that underlie distinct genetic or environmentally, i.e., pharmacological and lifestyle, induced renal transport deficits. Specifically, the ease of drug administration and the exploitation of improved genetic approaches might argue for the adoption of the zebrafish as a model for preclinical personalized medicine for distinct renal diseases and renal electrolyte transport proteins.

Zebrafish Model for Nonsyndromic X‐Linked Sensorineural Deafness, DFNX1

“…The zebrafish (Danio rerio) has become an increasingly important vertebrate model for human hearing disorders because it possesses a combination of powerful genetics, excellent embryology, and exceptional in vivo visualization in one organism (Ernest et al, 2000;Söllner et al, 2004;Whitfield et al, 2005;Nicolson, 2005;Millimaki et al, 2007;Schibler and Malicki, 2007;Gleason et al, 2009;Yariz et al, 2012;Diaz-Horta et al, 2014;Grati et al, 2015). It has many advantages for studying human diseases (Nicolson, 2005;Whitfield et al, 2005;Yariz et al, 2012;Kersten and Arjona, 2017;Lardelli et al, 2017;Ohki et al, 2017). First, low cost and space requirements make the zebrafish an excellent system for forward mutagenesis screens for defects in the inner ear and lateral line.…”

Modelling salt transport disorders of human kidney in zebrafish: the grain of salt

“…Once inside the cells, Na + ions are actively transported out of the cell by Na + –K + ‐ATPase, while Cl − streams through basolateral channels ClC‐Ka and ClC‐Kb. Because of their essential function, mutations in the genes encoding either NKCC2, ClC‐Kb or a β‐subunit of ClC‐K (barttin) cause disorders called Bartter's syndrome types I, III and IV, respectively (Kersten & Arjona, ).…”

“…Thus, the result suggests that chloride transport in zebrafish kidney might operate in different ways from that in humans and mice. While the orthologue of Nkcc2 is present in the distal tubule of zebrafish (Kersten & Arjona, ), the active channel that mediates the Na + and Cl − ions in the basolateral membrane remains unknown. Given the different cellular localization, zfclc‐k may also exert Cl − transport in a different context from its orthologues in humans and mice.…”

“…That compensation happens through a secondary aldosterone surge, which stimulates Na + reabsorption by the epithelial sodium channel (ENaC). In contrast, zebrafish do not express any orthologues of ENaC that enable compensation (Kersten & Arjona, ). Furthermore, the Na + reabsorption in the zebrafish collecting duct is independent of any mineralocorticoids.…”

“…). The zebrafish skin and ionocytes also express chloride ion channels and may take over the impaired chloride reabsorption in the kidney (Kersten & Arjona, ), although the study of Pérez‐Rius et al . () showed they could not compensate the effect of zfclc‐k knockout.…”