The positive effect of selective prostaglandin E2 receptor EP2 and EP4 blockade on cystogenesis in vitro is counteracted by increased kidney inflammation in vivo

Morgane Lannoy,Manoj K Valluru,Lijun Chang,Fatima Abdela-Ali,Dorien J.M Peters,Andrew J Streets,Albert C.M Ong

doi:10.1016/j.kint.2020.02.012

Morgane Lannoy, Manoj K Valluru + Show 5 more

Open Access

https://doi.org/10.1016/j.kint.2020.02.012

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Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major cause of end-stage kidney disease in man. The central role of cyclic adenosine monophosphate (cAMP) in ADPKD pathogenesis has been confirmed by numerous studies including positive clinical trial data. Here, we investigated the potential role of another major regulator of renal cAMP, prostaglandin E2 (PGE2), in modifying disease progression in ADPKD models using selective receptor modulators to all four PGE2 receptor subtypes (EP1-4). In 3D-culture model systems utilizing dog (MDCK) and patient-derived (UCL93, OX161-C1) kidney cell lines, PGE2 strikingly promoted cystogenesis and inhibited tubulogenesis by stimulating proliferation while reducing apoptosis. The effect of PGE2 on tubulogenesis and cystogenesis in 3D-culture was mimicked or abolished by selective EP2 and EP4 agonists or antagonists but not those specific to EP1 or EP3. In a Pkd1 mouse model (Pkd1nl/nl), kidney PGE2 and COX-2 expression were increased by two-fold at the peak of disease (week four). However, Pkd1nl/nl mice treated with selective EP2 (PF-04418948) or EP4 (ONO-AE3-208) antagonists from birth for three weeks had more severe cystic disease and fibrosis associated with increased cell proliferation and macrophage infiltration. A similar effect was observed for the EP4 antagonist ONO-AE3-208 in a second Pkd1 model (Pax8rtTA-TetO-Cre-Pkd1f/f). Thus, despite the positive effects of slowing cyst growth invitro, the more complex effects of inhibiting EP2 or EP4 invivo resulted in a worse outcome, possibly related to unexpected pro-inflammatory effects.

Highlights

Autosomal dominant polycystic kidney disease (ADPKD) is the most common kidney genetic disorder, accounting for 7–10% of patients with end-stage renal disease, and is caused by mutations in two genes, PKD1 (~85%) or PKD2 (~15%) 1
We investigated the potential role of another major regulator of renal cyclic adenosine monophosphate (cAMP), prostaglandin E2 (PGE2), in modifying disease progression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) models using selective receptor modulators to all four PGE2 receptor subtypes (EP1-4)
We report the effects of modifying PGE2 signalling on cyst growth by utilising new potent and selective receptor modulators to all four EP receptors (EP1-4) in cellular and animal models of ADPKD

Summary

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common kidney genetic disorder, accounting for 7–10% of patients with end-stage renal disease, and is caused by mutations in two genes, PKD1 (~85%) or PKD2 (~15%) 1 It is characterized by the formation of fluid-filled cysts which arise from tubular epithelial cells that exhibit a hyperproliferative and pro-apoptotic phenotype 2, 3. The administration of EP2 and EP4 antagonists to a neonatal model of ADPKD, the hypomophic Pkd[1] mouse (Pkd1nl/nl) and a post-natal Cre-inducible Pkd[1] model (Pax8rtTA-TetO-Cre-Pkd1f/f) led surprisingly to more severe cystic disease These results suggest a more complex effect of EP2 and EP4 antagonists in vivo resulting in a worse outcome in this model, possibly related to unexpected pro-inflammatory effects

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