title: From man to fish: What can Zebrafish tell us about ApoL1 nephropathy?
abstract: BACKGROUND
  Risk variant Apolipoprotein L1 (G1/G2) are strongly associated with a spectrum of kidney disease in people of recent African descent. The mechanism of ApoL1 nephropathy is unknown. Podocytes and/or endothelial cells are the presumed target kidney cells. Given the close homology in structure and function of zebrafish (ZF) pronephros and human nephron, we studied the effect of podocyte-specific or endothelium-specific expression of ApoL1 (G0, G1, or G2) on the structure and function of ZF pronephros.
  
  
  METHODS
  Wild type (G0) or risk variant ApoL1 (G1/G2) were expressed in podocyte-specific or endothelium-specific under podocin/Flk promoters, respectively, using Gal4-UAS system. Structural pronephric changes were studied with light and electron microscopy (EM). Proteinuria was assayed by measuring renal excretion of GFP-vitamin D binding protein. Puromycin aminonucleoside (PAN) was used as inducer of podocyte injury.
  
  
  RESULTS
  Endothelial-specific transgenic expression of G1/G2 is associated with endothelial injury indicated by endothelial cell swelling, segmental early double contours, and loss of endothelium fenestrae. Podocyte specific expression of G1 is associated with segmental podocyte foot process effacement and irregularities relative to G0. Despite the histological changes, the expression of G1/G2 alone in podocyte or endothelium compartment is not associated with edema, proteinuria, or gross whole fish phenotype. Moreover, PAN produced equal pericardial edema in all transgenic fish as well as nontransgenic controls.
  
  
  CONCLUSIONS
  Transgenic expression human ApoL1 (G1/G2) is associated with histologic abnormalities in ZF glomeruli but is insufficient to cause quantifiable renal dysfunction. This finding supports the necessity of a "second hit" in the pathogenesis/progression of ApoL1-associated nephropathy.
authors: Opeyemi
authors: O
authors: Olabisi
authors: Khaldoun
authors: K
authors: Al-Romaih
authors: Joel
authors: J
authors: Henderson
authors: Ritu
authors: R
authors: Tomar
authors: Iain
authors: I
authors: Drummond
authors: Calum
authors: C
authors: MacRae
authors: Martin
authors: M
authors: Pollak
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001053:Apolipoproteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007674:Kidney Diseases / Q000235:genetics*; D007678:Kidney Glomerulus / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D060910:Pronephros / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000652:urine; D014157:Transcription Factors / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D014809:Vitamin D-Binding Protein / Q000652:urine; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D001053:Apolipoproteins; D004268:DNA-Binding Proteins; C542436:Gal4 protein, zebrafish; D047908:Intracellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; C407223:NPHS2 protein; D014157:Transcription Factors; D014809:Vitamin D-Binding Protein; D029961:Zebrafish Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2