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EP1 receptor antagonism mitigates early and late stage renal fibrosis

Jean-Claude Kresse1, Henricus A M Mutsaers1, Michael Schou Jensen1

  • 1Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Acta Physiologica (Oxford, England)
|January 6, 2022
PubMed
Abstract

Insights

Targeting the EP1 receptor with SC-19220 effectively reduces renal fibrosis in preclinical models. This finding offers a promising therapeutic strategy for chronic kidney disease by inhibiting fibrogenesis.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Renal fibrosis is a primary driver of chronic kidney disease (CKD) progression.
  • Current treatments for CKD are limited in their ability to halt or reverse fibrogenesis.
  • The cyclooxygenase/prostaglandin system is implicated in renal injury and presents a potential therapeutic target.

Purpose of the Study:

  • To investigate the role of the prostaglandin E2 (PGE2)-EP1 receptor in the pathogenesis of renal fibrosis.
  • To evaluate the therapeutic potential of a selective EP1 receptor antagonist (SC-19220) in mitigating renal fibrosis.

Main Methods:

  • Utilized a translational approach involving mouse models (unilateral ureteral obstruction - UUO), human kidney slices (healthy and fibrotic), Madin-Darby Canine Kidney (MDCK) cells, and primary human renal fibroblasts (HRFs).
  • Assessed fibrosis markers at the gene and protein levels using quantitative polymerase chain reaction (qPCR), western blot, and immunostaining.
  • Administered the selective EP1 receptor antagonist SC-19220 to various models to determine its anti-fibrotic effects.

Main Results:

  • EP1 receptor inhibition with SC-19220 significantly reduced fibrosis in UUO mice, evidenced by decreased fibronectin (FN) and alpha-smooth muscle actin (αSMA) protein expression and collagen deposition.
  • In human kidney slices, SC-19220 treatment attenuated transforming growth factor-beta (TGF-β)-induced fibrosis, decreasing collagen 1A1, FN, and αSMA expression, along with collagen deposition.
  • SC-19220 demonstrated efficacy in reducing TGF-β-induced FN expression in both MDCK cells and human renal fibroblasts.

Conclusions:

  • The EP1 receptor is identified as a promising therapeutic target for both the initiation and progression of renal fibrosis.
  • The anti-fibrotic effects of SC-19220 observed in preclinical models, including human kidney tissue, suggest its potential for clinical translation in treating chronic kidney disease.
Keywords:
chronic kidney diseasehuman precision-cut kidney slicesprostaglandin E2 EP1 receptorrenal fibrosis

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