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

ABSTRACT: 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 ?M) reduced TGF-?-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 ?-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-?. The mechanism of action of butaprost appeared to be a direct effect on TGF-?/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.

SUBMITTER: Jensen MS

PROVIDER: S-EPMC6767420 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Activation of the prostaglandin E<sub>2</sub> EP<sub>2</sub> receptor attenuates renal fibrosis in unilateral ureteral obstructed mice and human kidney slices.

Jensen Michael Schou MS Mutsaers Henricus A M HAM Tingskov Stine Julie SJ Christensen Michael M Madsen Mia Gebauer MG Olinga Peter P Kwon Tae-Hwan TH Nørregaard Rikke R

Acta physiologica (Oxford, England) 20190520 1

<h4>Aim</h4>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 EP<sub>2</sub> receptor agonist, on renal fibrosis in several models of kidney injury, including human tissue slices.<h4>Methods</h4>We studied the an ...[more]

PMID: 31054202

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Project description:INTRODUCTION AND OBJECTIVE: Loss of renal function is often the impetus for operative intervention in renal obstruction. Obstructive nephropathy is characterized discrete morphological and physiologic changes including tubular dilatation, apoptosis, and atrophy, as well as interstitial cellular infiltration and progressive interstitial fibrosis. We hypothesize that there are gene expression alterations correlated with obstructive nephropathy that could serve as biomarkers for early intervention. METHODS: C57BL/6 mice were subjected to Unilateral Urethral Obstruction (UUO) or sham surgery at postnatal day 21 of life, and kidneys were harvested after 1, 2, 5 and 9 days postoperatively. RNA was extracted from kidneys and comprehensive gene expression profiling was performed with Agilent microarrays. We used biological replicates: 13 UUO replicates, 9 sham replicates. 2-Channel microarrays were hybridized using universal reference in the Cy3 channel. Ingenuity pathway analysis was used to analyze the biological function and gene networks of gene expression data. RESULTS: Microarray analysis revealed more than 1800 transcripts that were up- or down-regulated over days 1 through 9 following obstruction, and included many transcripts reported previously (FOS, CD44, CLU, SPP1 and EGF). Pathway analysis revealed significant enrichment of transcripts in cell activation/differentiation, immune/inflammatory responses, cell cycle, metabolic process and transport. Interestingly, IPA network analysis showed that transcriptional regulatory pathway involving CEBPB/HNF4A is involved in obstructive nephropathy. CONCLUSIONS: Transcript profiling identified numerous gene expression changes following UUO and suggests a role for CEBPB/HNF4A pathway in obstructive nephropathy. This dataset provides a foundation for development of biomarkers for obstructive nephropathy. Time: day samples were collected post operation Somatic Modification: mice were operated on to generate urethral obstruction (Obstructed/Control) time_series_design

Dataset Information

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

Publications

Activation of the prostaglandin E<sub>2</sub> EP<sub>2</sub> receptor attenuates renal fibrosis in unilateral ureteral obstructed mice and human kidney slices.

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