2020
DOI: 10.1016/j.kint.2019.11.016
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Transgenic zebrafish modeling low-molecular-weight proteinuria and lysosomal storage diseases

Abstract: 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… Show more

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Cited by 18 publications
(28 citation statements)
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References 50 publications
(60 reference statements)
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“…Studies in model organisms and congenital disorders including Donnai-Barrow syndrome, caused by mutations in the LRP2 gene coding for megalin, or Dent disease, caused by mutations in the CLCN5 gene coding for the endosomal chloride-proton exchanger ClC-5, have highlighted the critical role of megalin in the reabsorption of LMW ligands by PT cells. 24,25,30 Of note, alteration of megalin expression was also observed in patients with tenofovir-induced PT dysfunction, 31 confirming that the defect is not restricted to COVID-19. Conversely, the expression of megalin is preserved in patients presenting acute tubular injury without overt PT dysfunction, related, for example, to sepsis, aminoglycosides, or hepatorenal syndrome.…”
Section: Discussionmentioning
confidence: 77%
See 1 more Smart Citation
“…Studies in model organisms and congenital disorders including Donnai-Barrow syndrome, caused by mutations in the LRP2 gene coding for megalin, or Dent disease, caused by mutations in the CLCN5 gene coding for the endosomal chloride-proton exchanger ClC-5, have highlighted the critical role of megalin in the reabsorption of LMW ligands by PT cells. 24,25,30 Of note, alteration of megalin expression was also observed in patients with tenofovir-induced PT dysfunction, 31 confirming that the defect is not restricted to COVID-19. Conversely, the expression of megalin is preserved in patients presenting acute tubular injury without overt PT dysfunction, related, for example, to sepsis, aminoglycosides, or hepatorenal syndrome.…”
Section: Discussionmentioning
confidence: 77%
“…These lesions are associated with a ∼50% reduction in the apical staining for megalin in PT cells. Studies in model organisms and congenital disorders including Donnai-Barrow syndrome, caused by mutations in the LRP2 gene coding for megalin, or Dent disease, caused by mutations in the CLCN5 gene coding for the endosomal chloride-proton exchanger ClC-5, have highlighted the critical role of megalin in the reabsorption of LMW ligands by PT cells 24 , 25 , 30 . Of note, alteration of megalin expression in patients with COVID-19 was also observed in patients with tenofovir-induced PT dysfunction 31 , confirming the defect is not restricted to COVID-19.…”
Section: Discussionmentioning
confidence: 99%
“…Many of these disorders have been investigated in zebrafish due to the high evolutionary conservation of genes and proteins between zebrafish and humans. Furthermore, the model has particular advantages such as simple stainings and compound tracking, such as lysotracker, as well as specific transgenic lines that have been generated to track lysosomal processing [ 157 , 158 ].…”
Section: Lysosomal Storage Disordersmentioning
confidence: 99%
“…Recently the research group led by Chen et al 6 developed a zebrafish line that uses endogenous processes to assay for PT function without injection of a conjugated dye, expediting the ability to test many samples in a short amount of time. First, the researchers used TAL-ENs to create mutant lines for lrp2a Transmission electron microscopy of the mutants shows lrp2a mutants had fewer endocytic vesicles and clcn7 mutants had larger vesicles, providing evidence of successful mutagenesis of lrp2a (endocytosis defects) and clcn7 (lysosomal processing defects).…”
mentioning
confidence: 99%
“…For example, using the Tg(lfabp:: 1 / 2 vdbp-mCherry) line in a chemical screen with commonly prescribed drugs to identify those that affect PT function would lead to a better understanding of previously unknown factors that play a role in kidney dysfunction. Also, a similar approach to the studies of Chen et al 6 to rescue tubule function by treating mutants with a large number of molecules to rescue PT perturbations would uncover novel mechanisms of kidney protection.…”
mentioning
confidence: 99%