EP1 receptor antagonism mitigates early and late stage renal fibrosis

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DOI

AIM: Renal fibrosis is a major driver of chronic kidney disease, yet current treatment strategies are ineffective in attenuating fibrogenesis. The cyclooxygenase/prostaglandin system plays a key role in renal injury and holds great promise as a therapeutic target. Here, we used a translational approach to evaluate the role of the PGE2 -EP1 receptor in the pathogenesis of renal fibrosis in several models of kidney injury, including human (fibrotic) kidney slices.

METHODS: The anti-fibrotic efficacy of a selective EP1 receptor antagonist (SC-19220) was studied in mice subjected to unilateral ureteral obstruction (UUO), healthy and fibrotic human precision-cut kidney slices (PCKS), Madin-Darby Canine Kidney (MDCK) cells, and primary human renal fibroblasts (HRFs). Fibrosis was evaluated on gene and protein level using qPCR, Western Blot and immunostaining.

RESULTS: EP1 receptor inhibition diminished fibrosis in UUO mice, illustrated by a decreased protein expression of fibronectin (FN) and α-smooth muscle actin (αSMA) and a reduction in collagen deposition. Moreover, treatment of healthy human PCKS with SC-19220 reduced TGF-β-induced fibrosis as shown by decreased expression of collagen 1A1, FN and αSMA as well as reduced collagen deposition. Similar observations were made using fibrotic human PCKS. In addition, SC-19220 reduced TGF-β-induced FN expression in MDCK cells and HRFs.

CONCLUSION: This study highlights the EP1 receptor as a promising target for preventing both the onset and late stage of renal fibrosis. Moreover, we provide strong evidence that the effect of SC-19220 may translate to clinical care since its effects were observed in UUO mice, cells and human kidney slices.

Original languageEnglish
Article numbere13780
JournalActa Physiologica (Print)
Volume234
Issue3
Number of pages21
ISSN1748-1708
DOIs
Publication statusPublished - Mar 2022

    Research areas

  • DISRUPTION, EXPRESSION, INHIBITION, INJURY, PREVENTS DOWN-REGULATION, PROSTAGLANDIN E-2, REABSORPTION, SODIUM-TRANSPORT, SUBTYPE, URETERAL OBSTRUCTION, chronic kidney disease, human precision-cut kidney slices, prostaglandin E-2 EP1 receptor, renal fibrosis, prostaglandin E EP receptor

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