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Modulation of the secretory pathway rescues zebrafish polycystic kidney disease pathology.

Authors
  • Le Corre, Stéphanie1
  • Eyre, David2
  • Drummond, Iain A3
  • 1 Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts; and.
  • 2 Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington.
  • 3 Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts; and [email protected]
Type
Published Article
Journal
Journal of the American Society of Nephrology
Publisher
American Society of Nephrology
Publication Date
Aug 01, 2014
Volume
25
Issue
8
Pages
1749–1759
Identifiers
DOI: 10.1681/ASN.2013101060
PMID: 24627348
Source
Medline
License
Unknown

Abstract

Mutations in polycystin 1 and polycystin 2 are responsible for autosomal dominant polycystic kidney disease, the most common heritable human disease. Polycystins function as calcium ion channels, but their impact on cell physiology is not fully known. Recent findings suggest that polycystins could function in the maintenance of extracellular matrix integrity. In zebrafish, polycystin 2 knockdown induces kidney cysts, hydrocephalus, left/right asymmetry defects, and strong dorsal axis curvature. Here, we show that increased notochord sheath collagen deposition in polycystin 2-deficient embryos is directly linked to axis defects. Increased collagen II protein accumulation did not associate with increased col2a1 mRNA or a decrease in matrix metalloproteinase activity but, instead, it associated with increased expression of the endoplasmic reticulum/Golgi transport coat protein complex II Sec proteins. sec24D knockdown prevented dorsal axis curvature and kidney cystogenesis in polycystin 2 morphants. Nontoxic doses of brefeldin A also prevented the dorsal axis curvature formation in polycystin 2 morphants and curly up polycystin 2 mutants. Brefeldin A treatment after the onset of polycystin deficiency phenotypes reversed the curved axis phenotype but not kidney cyst progression. Our results suggest that polycystin 2 deficiency causes increased collagen II synthesis with upregulation of secretory pathway coat protein complex II components. Restoration of normal rates of secretory protein synthesis and secretion may be a new target in the treatment of autosomal dominant polycystic kidney disease.

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