Abstract: PO2456
Selective Activation of the Prostaglandin E2-EP4 Receptor Can Slow or Reverse the Fibrotic Process in Human Kidney Slices
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
- Jensen, Michael Schou, Aarhus Universitet, Aarhus, Midtjylland, Denmark
- Mutsaers, Henricus A.M., Aarhus Universitet, Aarhus, Midtjylland, Denmark
- Madsen, Mia Gebauer, Aarhus Universitetshospital, Aarhus, Denmark
- Norregaard, Rikke, Aarhus Universitet, Aarhus, Midtjylland, Denmark
Group or Team Name
- Nørregaard group
Background
Chronic kidney disease (CKD) affects approximately 10% of the population, and renal fibrosis, i.e. excessive scar formation in the kidney, is one of the major pathological processes leading to end-stage renal disease (ESRD). Despite overwhelming efforts to find therapies to reduce renal fibrosis, current management strategies are ineffective at preventing disease progression in CKD patients.
Activation of the prostaglandin E2-EP4 receptor has been shown to have renoprotective effects in cell and animal studies. However, translational studies using human kidney tissue are lacking.
Methods
In this project, we studied the anti-fibrotic effect of the selective EP4 receptor agonist Rivenprost using a translational model of renal fibrosis, namely human precision-cut kidney slices (PCKS). This model is ideal to study multicellular pathological processes, e.g. fibrosis, directly in human tissue, since cellular diversity and organ architecture is maintained in the slices. Macroscopically healthy renal tissue (n = 13) was obtained from tumor nephrectomies, whereas fibrotic renal tissue (n = 6) was obtained from ESRD nephrectomies. Subsequently, PCKS were incubated with Rivenprost (75µM) to evaluate its anti-fibrotic effect directly in human tissue. Fibrogenesis was evaluated on a gene level using qPCR. Viability was assessed by ATP measurements using ELISA. Protein and histological analyses are ongoing.
Results
The expression of the EP4 receptor in PCKS was increased twofold after 48h of incubation with the pro-fibrotic cytokine TGFβ, suggesting that the EP4 receptor might play a role in the fibrotic process. Treatment with Rivenprost mitigated TGFβ-induced fibrogenesis in healthy tissue. Moreover, Rivenprost halted disease progression in fibrotic PCKS and appeared to partly reverse fibrosis, as illustrated by a reduction in the gene expression of α-smooth muscle actin, fibronectin and collagen 1A1 by at least 50%, without affecting the viability of the human PCKS.
Conclusion
Selective stimulation of the PGE2-EP4 receptor can slow and reverse the process of fibrosis directly in human renal tissue. These findings warrant further research into the clinical application of Rivenprost, or other EP4 receptor agonists, as a treatment for (established) renal fibrosis.