Activation of the prostaglandin E-2 EP2 receptor attenuates renal fibrosis in unilateral ureteral obstructed mice and human kidney slices

Michael Schou Jensen, Henricus A. M. Mutsaers, Stine Julie Tingskov, Michael Christensen, Mia Gebauer Madsen, Peter Olinga, Tae-Hwan Kwon, Rikke Norregaard*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

17 Citaten (Scopus)
96 Downloads (Pure)

Samenvatting

Aim Renal 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. Methods We 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. Results Butaprost (50 mu M) reduced TGF-beta-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 alpha-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-beta. The mechanism of action of butaprost appeared to be a direct effect on TGF-beta/Smad signalling, which was independent of the cAMP/PKA pathway. Conclusion 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.

Originele taal-2English
Artikelnummere13291
Aantal pagina's13
TijdschriftActa physiologica
Volume227
Nummer van het tijdschrift1
Vroegere onlinedatum3-mei-2019
DOI's
StatusPublished - sep-2019

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