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 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. 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.

Translating kidney fibrosis: Role of the EP2 receptor

“…The authors show that butaprost attenuates TGF‐β‐induced fibrogenesis in precision‐cut human kidney slices. The also show that treating the human precision‐cut kidney slices with TGF‐β induces a fibrotic response, as evidenced by an increase in the expression of fibronectin, α‐smooth muscle actin and collagen 1A1 . These are the same fibrosis markers as were increased in the mouse model of unilateral ureteral obstruction.…”

“…The obstructed kidney reproducibly develops fibrosis in this in vivo mouse model. Butaprost attenuated the development of kidney fibrosis as assessed by a decrease in the expression of fibronectin, similar to the effect in MDCK cells, as well as α‐smooth muscle actin and collagen 1A1 . The authors begin administering butaprost on the day of surgery, not in advance of the obstruction.…”

“…In addition, the field has been hampered by the lack of good models that predict the ability of a potential therapy to translate to people. The paper by Jensen and colleagues in this issue of Acta Physiologica provides exciting advances that may help address both needs …”

Phenformin Attenuates Renal Injury in Unilateral Ureteral Obstructed Mice without Affecting Immune Cell Infiltration

“…It might be that the beneficial effects of phenformin are also present at non-toxic concentrations, as is seen in the field of cancer research [29]. Furthermore, it is worthwhile to investigate the potential synergistic effects of low doses of phenformin with other renoprotective agents such as butaprost or nintedanib [30,31].…”

D‐serine—A useful biomarker for renal injury?

“…Among these are studies about renal haemodynamics, [5][6][7] about potential prevention of acute kidney injury 8 or promising treatment of chronic kidney disease. 9,10 Investigations to understand, diagnose and treat renal diseases and renal damage are necessary and important for patients, society and public health care. 4 Moreover, biomarkers for fast and clear-cut detection of origin and location of renal damage still need to be established.…”