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Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
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The ADPKD genes pkd1a/b and pkd2 regulate extracellular matrix formation

Steve Mangos1, Pui-ying Lam, Angela Zhao

  • 1Massachusetts General Hospital, Department of Medicine, Nephrology Division, and Harvard Medical School Department of Genetics, Charlestown, MA 02129, USA.

Disease Models & Mechanisms
|March 26, 2010
PubMed

Insights

Polycystins (PKD1/PKD2) regulate extracellular matrix (ECM) integrity by controlling collagen gene expression. This discovery offers new insights into autosomal dominant polycystic kidney disease (ADPKD) pathologies.

Area of Science:

  • Genetics
  • Developmental Biology
  • Molecular Biology

Background:

  • Mutations in polycystin1 (PKD1) cause most autosomal dominant polycystic kidney disease (ADPKD) cases.
  • PKD1 mutations are linked to vascular and abdominal wall defects, suggesting polycystin1's role in extracellular matrix (ECM) integrity.

Purpose of the Study:

  • To investigate the role of polycystins (PKD1 paralogs pkd1a/b and PKD2) in axial morphogenesis and ECM regulation in zebrafish.
  • To elucidate the molecular mechanisms by which polycystins influence collagen gene expression and ECM assembly.

Main Methods:

  • Zebrafish knockdown models for pkd1a/b and pkd2.
  • Analysis of axial development, craniofacial structures, and pronephric cysts.
  • Assessment of collagen gene expression (col2a1) and collagen crosslinking.
  • Pharmacological inhibition of collagen crosslinking and PI3K signaling.

Main Results:

  • Combined knockdown of pkd1a/b and pkd2 caused dorsal axis curvature, hydrocephalus, and craniofacial defects, interacting in axial development.
  • Axis defects were linked to notochord collagen overexpression, reversible by col2a1 knockdown or collagen crosslinking inhibition.
  • pkd1a/b and pkd2 deficiency led to ectopic collagen mRNA expression, indicating a loss of negative feedback.
  • Polycystin knockdown sensitized embryos to collagen crosslinking inhibitors, and PI3K inhibition dysregulated col2a1 expression.

Conclusions:

  • pkd1a/b and pkd2 interact to regulate ECM secretion and assembly, potentially through a PI3K-dependent negative feedback pathway.
  • Altered ECM integrity due to polycystin dysfunction may be a primary defect in ADPKD.
  • These findings highlight a novel role for polycystins in matrix homeostasis relevant to ADPKD pathogenesis.

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