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Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease

Xia Zhou1, Lucy X Fan, William E Sweeney

  • 1Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.

The Journal of Clinical Investigation
|June 20, 2013
PubMed

Insights

Autosomal-dominant polycystic kidney disease (ADPKD) involves Sirtuin 1 (SIRT1) in kidney cyst development. Inhibiting SIRT1 slowed cyst growth in mouse models, offering new therapeutic targets for ADPKD.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Autosomal-dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by renal cyst formation, caused by mutations in PKD1 or PKD2.
  • The exact molecular mechanisms driving cystogenesis in ADPKD are not fully understood.

Purpose of the Study:

  • To investigate the role of nicotinamide adenine dinucleotide-dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) in the pathophysiology of ADPKD.
  • To evaluate the therapeutic potential of SIRT1 inhibition in ADPKD mouse models.

Main Methods:

  • Utilized Pkd1 mutant mouse models (embryonic, postnatal, hypomorphic) to study ADPKD.
  • Examined SIRT1 expression levels and its regulation by c-MYC and TNF-α.
  • Administered pan-sirtuin and SIRT1-specific inhibitors (nicotinamide, EX-527) to assess cyst growth.
  • Analyzed the impact of SIRT1 on cell proliferation and death via Rb and p53 pathways.

Main Results:

  • SIRT1 was upregulated in Pkd1-mutant renal epithelial cells and tissues.
  • Genetic deletion or pharmacological inhibition of SIRT1 significantly delayed renal cyst formation and growth in various Pkd1 mutant mouse models.
  • SIRT1 regulates cystic epithelial cell proliferation and apoptosis through deacetylation and phosphorylation of Rb and p53.

Conclusions:

  • SIRT1 plays a critical role in ADPKD pathogenesis by influencing cystic epithelial cell behavior.
  • Targeting SIRT1 signaling presents a promising therapeutic strategy for treating ADPKD.

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