Activation of the prostaglandin E2 EP2 receptor attenuates renal fibrosis in unilateral ureteral obstructed mice and human kidney slices.

Michael Schou Jensen,Henricus A M Mutsaers,Tae‐Hwan Kwon,Michael Christensen,Mia Gebauer Madsen,Peter Olinga,Rikke Nørregaard,Stine Julie Tingskov

doi:10.1111/apha.13291

Abstract

AimRenal fibrosis plays a pivotal role in the development and progression of chronic kidney disease, which affects 10% of the adult population. Previously, it has been demonstrated that the cyclooxygenase‐2 (COX‐2)/prostaglandin (PG) system influences the progression of renal injury. Here, we evaluated the impact of butaprost, a selective EP2 receptor agonist, on renal fibrosis in several models of kidney injury, including human tissue slices.MethodsWe studied the anti‐fibrotic efficacy of butaprost using Madin‐Darby Canine Kidney (MDCK) cells, mice that underwent unilateral ureteral obstruction and human precision‐cut kidney slices. Fibrogenesis was evaluated on a gene and protein level by qPCR and Western blotting.ResultsButaprost (50 μM) reduced TGF‐β‐induced fibronectin (FN) expression, Smad2 phosphorylation and epithelial‐mesenchymal transition in MDCK cells. In addition, treatment with 4 mg/kg/day butaprost attenuated the development of fibrosis in mice that underwent unilateral ureteral obstruction surgery, as illustrated by a reduction in the gene and protein expression of α‐smooth muscle actin, FN and collagen 1A1. More importantly, a similar anti‐fibrotic effect of butaprost was observed in human precision‐cut kidney slices exposed to TGF‐β. The mechanism of action of butaprost appeared to be a direct effect on TGF‐β/Smad signalling, which was independent of the cAMP/PKA pathway.ConclusionIn conclusion, this study demonstrates that stimulation of the EP2 receptor effectively mitigates renal fibrogenesis in various fibrosis models. These findings warrant further research into the clinical application of butaprost, or other EP2 agonists, for the inhibition of renal fibrosis.

Highlights

Chronic kidney disease (CKD) affects approximately 10% of the adult population in developed countries.[1]
As inhibition of adenylate cyclase (AC) did not attenuate the effects of butaprost, we investigated if protein kinase A (PKA), the cAMP‐ dependent activator of cAMP response element‐binding protein (CREB), was involved in its activity
Exposure of Madin‐Darby Canine Kidney (MDCK) cells to a combination of TGF‐β, butaprost and H89 did not reverse the anti‐fibrotic effect of butaprost (Figure 2C). These findings suggest that the impact of butaprost on fibrogenesis is unconstrained by the cAMP/ PKA signalling pathway

Summary

Introduction

Chronic kidney disease (CKD) affects approximately 10% of the adult population in developed countries.[1]. It has been reported that EP1 deletion in mice reduced diabetes‐induced expression of the fibrotic markers fibronectin and α‐actin.[7] EP1 antagonism, using ONO8711, decreased fibronectin (FN) expression in mouse proximal tubule cells.[7] In addition, deletion of EP2 increases baseline systolic blood pressure and causes salt‐sensitive hypertension, which is a known risk factor for renal damage.[8] Interestingly, renal gene expression of both EP2 and EP4 is shown to be increased during renal fibrogenesis, suggesting that these receptors might play a protective role in the fibrotic process.[4,9] This notion is supported by the fact that butaprost, a selective EP2 agonist, inhibits TGF‐β1‐induced myofibroblast transition of human foetal lung fibroblasts.[10] the efficacy of butaprost for the treatment of renal fibrosis remains to be elucidated

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