PUBLICATION

Characterizing renal involvement in Hermansky-Pudlak Syndrome in a zebrafish model

Authors
Schenk, H., Müller-Deile, J., Schroder, P., Bolaños-Palmieri, P., Beverly-Staggs, L., White, R., Bräsen, J.H., Haller, H., Schiffer, M.
ID
ZDB-PUB-191130-2
Date
2019
Source
Scientific Reports   9: 17718 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Cell Line
  • Cells, Cultured
  • Disease Models, Animal*
  • Endothelial Cells/metabolism
  • Endothelium, Vascular/cytology
  • Hermanski-Pudlak Syndrome/genetics*
  • Hermanski-Pudlak Syndrome/metabolism
  • Hermanski-Pudlak Syndrome/pathology
  • Humans
  • Kidney/metabolism
  • Kidney/pathology*
  • Lysosomes/metabolism
  • Lysosomes/pathology
  • Podocytes/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics*
PubMed
31776394 Full text @ Sci. Rep.
Abstract
Hermansky-Pudlak Syndrome (HPS) is a rare disease caused by mutations in the genes coding for various HPS proteins. HPS proteins are part of multi-subunit complexes involved in the biogenesis of organelles from the lysosomal-endosomal-system. In humans, this syndrome is characterized by the presence of albinism, platelet dysfunction and pulmonary fibrosis. The renal component to the disease remains unstudied and untreated in patients with HPS. Here we demonstrate that in humans, HPS proteins have a high renal expression with active transcription of HPS1, 3, 4 and 5 in human podocyte cell culture, suggesting that impaired function of HPS proteins could directly impact renal function. Therefore, we developed a zebrafish model to study the renal involvement of HPS proteins in proteinuric kidney disease. Remarkably, knockdown of HPS genes in zebrafish causes glomerular injury with edema, proteinuria and structural changes of the glomerular filtration barrier. Moreover, reduced expression of HPS proteins in zebrafish recapitulates other important disease hallmarks, like hypopigmentation and accumulation of intracellular debris characteristic of lysosomal disorders. In conclusion, we present a valid zebrafish model that highlights the previously underestimated relevance of renal disease in HPS. This draws attention to the therapeutic options available to manage this component of the syndrome.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping