Abstract: PO2467
Multitarget Soluble Epoxide Hydrolase/Farnesoid X Receptor Agonist Combats CKD
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
Author
- Imig, John D., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background
Chronic kidney disease (CKD) is characterized by progressive fibrosis leading to end-stage renal disease. There has been little success in developing agents that can slow the progression of CKD to ESRD. The current study investigated the efficacy of an innovative multi-target ligand drug, DM509, in mitigating renal fibrosis using the unilateral ureteral obstruction (UUO) mouse CKD model.
Methods
DM509 acts concurrently as a soluble epoxide hydrolase inhibitor and farnesoid X receptor agonist. UUO or sham surgery was conducted in C57BL/6J male mice (n=8/group). Interventional DM509 treatment (10 mg/kg/d p.o.) or vehicle was started three days after UUO induction and continued for 7 days. Plasma and kidney tissue were collected at the end of the experimental protocol. Several biochemical, histopathological, immunohistopathological, and gene expression studies were carried out to determine the antifibrotic actions for DM509
Results
UUO mice demonstrated fibrosis with higher kidney hydroxyproline content (267±46 vs. 53±14 µg/mg protein), collagen area (4.3±0.1% vs. 0.7±0.3%). DM509 reduced hydroxyproline by 41% and collagen area by 65%. Renal inflammation was evident in UUO mice with elevated MCP-1, increased CD45 immune cells, and increased TNF-a, IL-6, IL-1b expression. Interventional DM509 treatment markedly reduced renal inflammation in UUO mice. Vascular inflammation was evident in UUO mice with increased higher ICAM and VCAM expression. DM509 reduced vascular inflammation by 40-50% in UUO mice. In addition, peritubular vascular density assessed by CD31 was reduced by 35% in UUO mice and DM509 attenuated vascular loss. Kidney fibrosis in UUO mice was associated with epithelial-to-mesenchymal transition (EMT) with higher expression of mesenchymal markers a-SMA, FSP-1, and FN, as well as a marked decrease in the epithelial marker, E-cadherin. UUO mice treated with DM509 had markedly reduced EMT. UUO mice also had tubular epithelial barrier injury with increased renal KIM-1, NGAL expression and lower claudin-1, -2 and -4 expression. DM509 treatment reduced tubular injury markers by 25-50% and maintained tubular epithelial integrity by restoring claudin expression in UUO mice.
Conclusion
These data reveal that DM509 is a promising multi-target antifibrotic drug that combats epithelial and vascular kidney fibrotic disease and CKD progression.
Funding
- NIDDK Support