ZFIN ID: ZDB-PUB-200221-2
Transgenic zebrafish modeling low-molecular-weight proteinuria and lysosomal storage diseases
Chen, Z., Luciani, A., Mateos, J.M., Barmettler, G., Giles, R.H., Neuhauss, S.C.F., Devuyst, O.
Date: 2019
Source: Kidney International   97(6): 1150-1163 (Journal)
Registered Authors: Devuyst, Oliver, Luciani, Alessandro, Neuhauss, Stephan
Keywords: endocytosis, lysosome, model organism, proximal tubule, renal Fanconi syndrome
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Endocytosis
  • Humans
  • Kidney Tubules, Proximal
  • Low Density Lipoprotein Receptor-Related Protein-2/genetics
  • Lysosomal Storage Diseases*
  • Proteinuria/chemically induced
  • Proteinuria/genetics
  • Zebrafish*/genetics
PubMed: 32061435 Full text @ Kidney Int.
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ABSTRACT
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.
ADDITIONAL INFORMATION