Dataset Information

EP₁ receptor antagonism mitigates early and late stage renal fibrosis.

ABSTRACT:

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.

SUBMITTER: Kresse JC

PROVIDER: S-EPMC9286353 | biostudies-literature |

REPOSITORIES: biostudies-literature

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EP₁ receptor antagonism mitigates early and late stage renal fibrosis.

Aim

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EP₁ receptor antagonism mitigates early and late stage renal fibrosis.