Kidney Week

Abstract: TH-PO566

Prostaglandin E2 Stimulates Cyst Expansion and Induces Cyst Formation in ADPKD

Session Information

• Cystic Kidney Diseases - I
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Lannoy, Morgane, University of Sheffield, Sheffield, United Kingdom

Morgane Lannoy,

• Chang, Lijun, University of Sheffield, Sheffield, United Kingdom

Lijun Chang,

• Abdela-Ali, Fatma, University of Sheffield, Sheffield, United Kingdom

Fatma Abdela-Ali,

• Peters, Dorien J.M., Leiden University Medical Center, Leiden, Netherlands

Dorien J.M. Peters,

• Streets, Andrew J., University of Sheffield, Sheffield, United Kingdom

Andrew J. Streets,

• Ong, Albert C., University of Sheffield, Sheffield, United Kingdom

Albert C. Ong,

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major cause of kidney failure in man. Although multiple signalling pathways have been implicated in ADPKD pathogenesis, there is a general consensus that cyclic AMP (cAMP) signalling plays a central role in disease progression. Clinical trials lowering renal cAMP levels with a vasopressin 2 receptor antagonist, or a somatostatin agonist, have shown positive effects in slowing disease progression. Here, we report that selective blockade of prostaglandin E₂ (PGE₂) action, could be an alternative or adjunctive therapeutic strategy in ADPKD, through reducing cAMP.

Methods

cAMP, PGE₂ and its receptors (EP1-4) were analysed by qPCR, ELISA, immunoblotting and immunohistochemistry (IHC) on human cystic cell lines, human ADPKD kidney tissue and two mouse models of ADPKD. The functional effects of selective PGE₂ receptor agonists and antagonists on cyst growth were studied using 3D cyst assays in three cellular models.

Results

EP2 and EP4 mRNA were significantly elevated in cystic kidneys from two murine models of ADPKD (Pkd1^nl/nl, Pkd1-iKspCre). PGE₂ and cAMP were also found upregulated in Pkd1^nl/nl at the peak of the disease. The overexpression of EP2 and EP4 were confirmed in human ADPKD kidney tissue by IHC. There was differential upregulation of EP2 in a panel of human cystic lines. PGE₂ stimulated a significant increase in cyst growth in dog (MDCKII), human (OX161) and mouse (F1/CRE) cells in a dose-dependent manner. This effect was mediated by EP2 and EP4 since its action was blocked by selective antagonists and reproduced by selective agonists in the absence of PGE₂. The effects of PGE₂, EP2 and EP4 agonists on cyst growth were closely correlated with increased proliferation and decreased apoptosis. Strikingly, PGE₂ was able to transform tubular structures formed by a non-cystic human kidney cell line (UCL93) in 3D culture to a predominant cystic phenotype. Current work is investigating the effect of EP2 and EP4 antagonists on cyst initiation and disease progression in vivo.

Funding

• Private Foundation Support