Zebrafish as a model for kidney function and disease

Outtandy, Priya; Russell, Claire; Kleta, Robert; Böckenhauer, Detlef

doi:10.1007/s00467-018-3921-7

Cited by 72 publications

(51 citation statements)

References 99 publications

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“…As they are labor-intensive, the injection methods do not allow largescale assessment of PT dysfunction in larvae or adult zebrafish models. Detecting biomarkers in fish urine is difficult, as such markers are diluted in the pool, 18 and filtration/processing of endogenous LMW proteins has not been characterized. We hypothesized that these difficulties could be overcome with a transgenic zebrafish reporter line expressing a fluorescent, LMW protein amenable to PT endocytosis and processing.…”

Section: Translational Statementmentioning

confidence: 99%

Transgenic zebrafish modeling low-molecular-weight proteinuria and lysosomal storage diseases

Chen

Luciani

Mateos

et al. 2020

Kidney International

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Epithelial cells lining the proximal tubule of the kidney reabsorb and metabolize most of the filtered lowmolecular-weight proteins through receptor-mediated endocytosis and lysosomal processing. Congenital and acquired dysfunctions of the proximal tubule are consistently reflected by the inappropriate loss of solutes including low-molecular-weight proteins in the urine. The zebrafish pronephros shares individual functional segments with the human nephron, including lrp2a/ megalin-dependent endocytic transport processes of the proximal tubule. Although the zebrafish has been used as a model organism for toxicological studies and drug discovery, there is no available assay that allows large-scale assessment of proximal tubule function in larval or adult stages. Here we establish a transgenic Tg(lfabp:: 1 / 2 vdbp-mCherry) zebrafish line expressing in the liver the Nterminal region of vitamin D-binding protein coupled to the acid-insensitive, red monomeric fluorescent protein mCherry (1 / 2 vdbp-mCherry). This low-molecular-weight protein construct is secreted into the bloodstream, filtered through the glomerulus, reabsorbed by receptor-mediated endocytosis and processed in the lysosomes of proximal tubule cells of the fish. Thus, our proof-of-concept studies using zebrafish larvae knockout for lrp2a and clcn7 or exposed to known nephrotoxins (gentamicin and cisplatin) demonstrate that this transgenic line is useful to monitor low-molecular-weight proteinuria and lysosomal processing. This represents a powerful new model organism for drug screening and studies of nephrotoxicity.

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Section: Translational Statementmentioning

confidence: 99%

Transgenic zebrafish modeling low-molecular-weight proteinuria and lysosomal storage diseases

Chen

Luciani

Mateos

et al. 2020

Kidney International

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show abstract

“…• Glomeruli, proximal/distal tubules, collecting ducts, and brush border membrane are present (Menke et al, 2011;Outtandy et al, 2019) • Major solute transporters and receptors are present (Outtandy et al, 2019) • Pronephros rather than metanephros (Outtandy et al, 2019) Liver…”

Section: Geneticsmentioning

confidence: 99%

Modeling Lysosomal Storage Diseases in the Zebrafish

Peterson

2020

Front. Mol. Biosci.

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Lysosomal storage diseases (LSDs) are a family of 70 metabolic disorders characterized by mutations in lysosomal proteins that lead to storage material accumulation, multipleorgan pathologies that often involve neurodegeneration, and early mortality in a significant number of patients. Along with the necessity for more effective therapies, there exists an unmet need for further understanding of disease etiology, which could uncover novel pathways and drug targets. Over the past few decades, the growth in knowledge of disease-associated pathways has been facilitated by studies in model organisms, as advancements in mutagenesis techniques markedly improved the efficiency of model generation in mammalian and non-mammalian systems. In this review we highlight non-mammalian models of LSDs, focusing specifically on the zebrafish, a vertebrate model organism that shares remarkable genetic and metabolic similarities with mammals while also conferring unique advantages such as optical transparency and amenability toward high-throughput applications. We examine published zebrafish LSD models and their reported phenotypes, address organismspecific advantages and limitations, and discuss recent technological innovations that could provide potential solutions.

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“…In human and murine organisms, the pronephros and mesonephros are transient organs and degenerate at the embryonic stage [ 2 ]. Unlike in lower vertebrates, such as zebrafish and Xenopus, where the pronephros is functional at the embryonic and larval stages [ 24 , 25 ], the metanephros begins at E 32 in human and E 10.5 in mice [ 26 ]. Notably, the metanephros is permanent and will develop into a functional adult kidney in mammals.…”

Section: Wnt Signaling In Kidney Developmentmentioning

confidence: 99%

Wnt signaling in kidney: the initiator or terminator?

et al. 2020

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The kidney is a key organ in the human body that excretes toxins and sustains the water–electrolyte balance. During embryonic development and disease progression, the kidney undergoes enormous changes in macrostructure, accompanied by a variety of microstructural histological changes, such as glomerular formation and sclerosis, tubule elongation and atrophy, interstitial establishment, and fibrosis progression. All of these rely on the frequent occurrence of cell death and growth. Notably, to overcome disease, some cells regenerate through self-repair or progenitor cell differentiation. However, the signaling mechanisms underlying kidney development and regeneration have not been elucidated. Recently, Wnt signaling has been noted to play an important role. Although it is a well-known developmental signal, the role of Wnt signaling in kidney development and regeneration is not well recognized. In this review, we review the role of Wnt signaling in kidney embryonic development, tissue repair, cell division, and progenitor cell differentiation after injury. Moreover, we briefly highlight advances in our understanding of the pathogenic mechanisms of Wnt signaling in mediating cellular senescence in kidney parenchymal and stem cells, an irreversible arrest of cell proliferation blocking tissue repair and regeneration. We also highlight the therapeutic targets of Wnt signaling in kidney diseases and provide important clues for clinical strategies.

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Zebrafish as a model for kidney function and disease

Cited by 72 publications

References 99 publications

Transgenic zebrafish modeling low-molecular-weight proteinuria and lysosomal storage diseases

Transgenic zebrafish modeling low-molecular-weight proteinuria and lysosomal storage diseases

Modeling Lysosomal Storage Diseases in the Zebrafish

Wnt signaling in kidney: the initiator or terminator?

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