Kidney Week

Abstract: PO2455

EP1 Receptor Antagonism Mitigates Early and Late-Stage Renal Fibrosis

Session Information

• CKD: Inflammation, Endothelial Dysfunction, and Signaling
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2103 CKD (Non-Dialysis): Mechanisms

Authors

• Kresse, Jean-Claude, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Jean-Claude Kresse, MS

• Mutsaers, Henricus A.M., Aarhus Universitet, Aarhus, Midtjylland, Denmark

Henricus A.M. Mutsaers,

• Jensen, Michael Schou, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Michael Schou Jensen,

• Tingskov, Stine Julie Hyldal, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Stine Julie Hyldal Tingskov,

• Madsen, Mia Gebauer, Aarhus Universitetshospital, Aarhus, Denmark

Mia Gebauer Madsen,

• Norregaard, Rikke, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Rikke Norregaard,

Background

Renal fibrosis is a hallmark of Chronic Kidney Disease (CKD), which affects 10-16% of the world’s adult population. Yet current treatment strategies are ineffective in attenuating renal fibrogenesis. Therefore, we are in urgent need for new therapeutic strategies against renal fibrosis. The cyclooxygenase/prostaglandin (COX/PG) system plays a key role in renal fibrosis and holds great promise as a suitable 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 effect of SC-19220 - an EP₁ receptor antagonist - was studied in Madin-Darby Canine Kidney (MDCK) cells, mice subjected to seven days of unilateral ureteral obstruction (UUO), and healthy and fibrotic human precision-cut kidney slices (PCKS). Progression of fibrosis was evaluated on gene and protein level using qPCR, Western blot and immunohistochemistry.

Results

Pharmacological inhibition of the EP₁ receptor using SC-19220 reduced TGF-β-induced fibronectin (FN) expression, ERK1/2 phosphorylation and epithelial-to-mesenchymal transition in MDCK cells. Moreover, SC-19220 diminished fibrosis in UUO mice, measured by decreased protein expression of FN and α-smooth muscle actin (αSMA), and a reduction in collagen deposition. In addition, treatment of healthy human PCKS with SC-19220 reduced TGF-β-induced fibrosis as shown by decreased gene levels of collagen 1A1, FN and αSMA as well as reduced collagen deposition. Moreover, similar observations were made using fibrotic human PCKS.

Conclusion

This study highlights that the EP₁ receptor is 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 and human kidney slices.