Administration of a selective prostaglandin E2 receptor agonist attenuates renal fibrosis in vitro and in vivo

Abstract

Renal fibrosis plays a pivotal role in the development and progression of chronic kidney disease (CKD), 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. PGE2 interacts with four different G‐protein‐coupled PGE2 EP receptors, known as EP1–EP4, and plays a role in several biological functions. Previous studies show that the EP2 receptor is involved in progression of lung fibrosis. In this study, we investigated the effect of an EP2 agonist (butaprost) on renal fibrogenesis on a cellular, renal tissue and organismal level using well‐established in vivo and in vitro models as well as a recently developed human model of renal fibrosis. This model is ideal to study multicellular pathological processes, e.g. fibrosis, directly in human tissue since cellular diversity and organ architecture is maintained in the slices. Butaprost (50 μM) reduced TGF‐β‐induced fibronectin (FN) expression, Smad2/3 phosphorylation and epithelial‐mesenchymal transition in MDCK cells. In addition, treatment with 4 mg/kg butaprost attenuated the development of fibrosis in mice that underwent unilateral ureteral obstruction (UUO) surgery, as illustrated by a significant 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 signaling, which was independent of the cAMP/PKA pathway. In 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.Support or Funding Information Sources of support: This work was kindly supported by Lundbeckfonden, grant number R231‐2016‐2344 as well as the Danish Council for Independent Research, grant number 6110‐00231B, Aarhus University Research Foundation, grant number AUFF‐E‐2015‐FLS‐8‐69 and Hildur and Dagny Jacobsens Foundation grant number 1295716‐1.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.