Transgenic zebrafish modeling low-molecular-weight proteinuria and lysosomal storage diseases.
- Chen Z Institute of Physiology, University of Zurich, Zurich, Switzerland.
- Luciani A Institute of Physiology, University of Zurich, Zurich, Switzerland.
- Mateos JM Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland.
- Barmettler G Center for Microscopy and Image Analysis, University of Zurich, Zurich, Switzerland.
- Giles RH Department of Nephrology and Hypertension, Hubrecht Institute, Utrecht, The Netherlands; University Medical Center Utrecht, Utrecht, The Netherlands.
- Neuhauss SCF Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
- Devuyst O Institute of Physiology, University of Zurich, Zurich, Switzerland. Electronic address: olivier.devuyst@uzh.ch.
- 2020-02-17
Published in:
- Kidney international. - 2020
English
Epithelial cells lining the proximal tubule of the kidney reabsorb and metabolize most of the filtered low-molecular-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::½vdbp-mCherry) zebrafish line expressing in the liver the N-terminal region of vitamin D-binding protein coupled to the acid-insensitive, red monomeric fluorescent protein mCherry (½vdbp-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.
- Language
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- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1016/j.kint.2019.11.016
- PMID 32061435
- Persistent URL
- https://sonar.ch/global/documents/174914
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