title: Modulation of the secretory pathway rescues zebrafish polycystic kidney disease pathology.
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.
authors.affiliation: Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts; and.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Corre
authors.affiliation: Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington.
authors.forename: David
authors.initials: D
authors.lastname: Eyre
authors.affiliation: Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts; and idrummond@partners.org.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Drummond
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D020126:Brefeldin A / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology; D024043:Collagen Type II / Q000378:metabolism; D009672:Notochord / Q000378:metabolism / Q000473:pathology; D007690:Polycystic Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D055571:Secretory Pathway / Q000187:drug effects / Q000502:physiology*; D050396:TRPP Cation Channels / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*
chemical_list: D020126:Brefeldin A; D002352:Carrier Proteins; D024043:Collagen Type II; D011500:Protein Synthesis Inhibitors; D050396:TRPP Cation Channels; D033921:Vesicular Transport Proteins; D029961:Zebrafish Proteins