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Updated: May 2, 2026
A Possible Zebrafish Model of Polycystic Kidney Disease: Knockdown of wnt5a Causes Cysts in Zebrafish Kidneys
Published on: December 2, 2014
Modulation of the secretory pathway rescues zebrafish polycystic kidney disease pathology
Stéphanie Le Corre1, David Eyre2, Iain A Drummond3
1Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts; and.
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.
Insights
Polycystin 2 deficiency in zebrafish causes kidney cysts and axis defects by increasing collagen II synthesis. Targeting the secretory pathway may offer new treatments for autosomal dominant polycystic kidney disease.
Area of Science:
- Cell Biology
- Developmental Biology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human disorder, caused by mutations in polycystin 1 or polycystin 2.
- Polycystins are calcium ion channels, but their precise roles in cell physiology and disease pathogenesis remain incompletely understood.
- Emerging evidence suggests polycystins are involved in maintaining extracellular matrix integrity.
Purpose of the Study:
- To investigate the cellular mechanisms underlying polycystin 2 deficiency-induced developmental defects in zebrafish.
- To determine the link between polycystin 2 function, extracellular matrix deposition, and axis formation.
- To explore potential therapeutic targets for ADPKD by examining the secretory pathway's role.
Main Methods:
- Zebrafish models with polycystin 2 knockdown (morphants) and mutations were utilized.
- Collagen II deposition, mRNA levels (col2a1), matrix metalloproteinase activity, and secretory pathway components (Sec proteins) were analyzed.
- Intervention with sec24D knockdown and brefeldin A (a secretory pathway inhibitor) was performed.
Main Results:
- Polycystin 2 deficiency led to increased notochord sheath collagen II deposition, correlating with dorsal axis curvature and kidney cyst formation.
- Increased collagen II protein accumulation was observed without changes in col2a1 mRNA or matrix metalloproteinase activity.
- Upregulation of endoplasmic reticulum/Golgi transport coat protein complex II (Sec) proteins was associated with polycystin 2 deficiency.
- sec24D knockdown and brefeldin A treatment ameliorated axis defects and kidney cystogenesis in polycystin 2-deficient zebrafish.
- Brefeldin A reversed axis curvature but not kidney cyst progression when administered after phenotype onset.
Conclusions:
- Polycystin 2 deficiency disrupts extracellular matrix homeostasis, specifically collagen II synthesis and secretion, via the secretory pathway.
- The secretory pathway, particularly Sec proteins, plays a critical role in polycystin 2-dependent developmental processes.
- Modulating secretory protein synthesis and transport presents a potential therapeutic strategy for ADPKD.
