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Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1

Benjamin S Freedman1, Albert Q Lam, Jamie L Sundsbak

  • 1Renal Division and Harvard Center for Polycystic Kidney Disease Research, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;

Journal of the American Society of Nephrology : JASN
|September 7, 2013
PubMed

Insights

Autosomal dominant polycystic kidney disease (ADPKD) arises from PKD1 mutations, impacting polycystin-1 (PC1) and polycystin-2 (PC2) levels. Induced pluripotent stem cells reveal PC1 regulates ciliary PC2, offering insights into PKD pathogenesis.

Area of Science:

  • Nephrology
  • Genetics
  • Stem Cell Biology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are genetic kidney disorders caused by mutations in PKD1/PKD2 and PKHD1, respectively.
  • The precise relationship between polycystin-1 (PC1), polycystin-2 (PC2), and fibrocystin/polyductin (FPC) in polycystic kidney disease (PKD) pathogenesis remains incompletely understood.
  • Modeling PKD in human cells is crucial for dissecting disease mechanisms.

Purpose of the Study:

  • To establish and characterize induced pluripotent stem (iPS) cell models from ADPKD and ARPKD patients.
  • To investigate the functional relationship between PC1, PC2, and FPC in PKD.
  • To explore the potential of iPS cells for studying PKD pathophysiology.

Main Methods:

  • Generation of iPS cell lines from fibroblasts of ADPKD and ARPKD patients.
  • Genetic sequencing to confirm mutations in PKD1.
  • Analysis of primary cilia structure and protein expression (PC1, PC2, FPC) in undifferentiated and differentiated iPS cells.
  • Assessment of proliferation, apoptosis, and ciliogenesis rates.
  • Ectopic expression studies to evaluate the rescue effect of wild-type PC1.

Main Results:

  • PKD iPS cells retained the heterozygous PKD1 mutations found in parental fibroblasts.
  • ADPKD iPS cells and their differentiated progeny showed reduced PC2 levels in primary cilia.
  • Ectopic expression of wild-type PC1 restored normal ciliary PC2 levels in ADPKD iPS-derived cells.
  • PC1, but not a truncated mutant, increased ciliary PC2 levels in mouse kidney cells.

Conclusions:

  • Polycystin-1 (PC1) plays a regulatory role in controlling ciliary polycystin-2 (PC2) protein levels.
  • These findings highlight a potential mechanism contributing to ADPKD pathogenesis.
  • PKD patient-derived iPS cells are a valuable tool for investigating PKD mechanisms and potential therapeutic targets.

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