Prostaglandin E2 mediates proliferation and chloride secretion in ADPKD cystic renal epithelia

Yu Liu, Madhumitha Rajagopal, Kim Lee, Lorenzo Battini, Daniel Flores, G. Luca Gusella, Alan C. Pao, Rajeev Rohatgi

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Prostaglandin E2 (PGE2) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE2 induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE2 induces proliferation and chloride (Cl-) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl- secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE2 in cell proliferation. Exogenous administration of PGE2 increased proliferation of PC-1-deficient cells by 38.8 ± 5.2% (P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 ± 1.9% (P < 0.05). Next, we tested whether PGE2-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream β-catenin activation. PGE2 and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active β-catenin in PC-1-deficient cells, suggesting a mechanism for PGE2-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE2-dependent Cl- secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current (I sc). Addition of PGE2 induced a fivefold higher increase in I sc in PC-1-deficient cells compared with PC-1-replete cells. This PGE2-induced increase in I sc in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE2 activates CFTR and calcium-activated Cl- channels. In conclusion, PGE2 activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE2 inhibition and EP4 receptor antagonism.

Original languageEnglish
Pages (from-to)F1425-F1434
JournalAmerican Journal of Physiology - Renal Physiology
Issue number10
StatePublished - 2012


  • Cyclooxygenase
  • Cystic epithelia
  • Prostanoid
  • Secretory renal epithelia


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