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Kidney Week

Abstract: FR-PO550

The Cilia-Enriched Oxysterol 7β,27-DHC Is Required for Polycystin Activation

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Ha, Kotdaji, University of California San Francisco, San Francisco, California, United States
  • Mundt, Nadine, University of California San Francisco, San Francisco, California, United States
  • Pinedo, Aide, University of California San Francisco, San Francisco, California, United States
  • Loeb, Gabriel, University of California San Francisco, San Francisco, California, United States
  • Reiter, Jeremy, University of California San Francisco, San Francisco, California, United States
  • Delling, Markus, University of California San Francisco, San Francisco, California, United States
Background

The polycystin complex (PC-1 and PC-2) forms a non-selective cation channel and mutations within the polycystin complex cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane is poorly understood, partially due to technical limitations studying the electrical properties of this tiny cellular compartment.

Methods

In this study, we used both whole-cell and ciliary patch-clamp recordings to measure the polycystin activity in the plasma or ciliary membrane. For carbenoxolone (CNX) injection study, we used intravenous and intraperitoneal injections to C57BL/6 strain mice from postnatal day 0.5 to 17.

Results

We identified a novel oxysterol binding pocket within PC-2 to modulate channel activation and showed that mutations within the oxysterol binding pocket disrupt 7β,27-DHC dependent polycystin activation. Pharmacologic and genetic inhibition of 11B-HSD enzyme that synthesizes oxysterol deplete channel activity in primary cilia and result in renal tubular dilation in vivo.

Conclusion

Our results identify the oxysterol binding pocket in PC-2 as an allosteric regulatory site in the polycystin complex, which may provide a specific target for novel ADPKD therapeutics.

Funding

  • NIDDK Support