Key result
Interventional DM509 treatment reduced kidney hydroxyproline content by 41% and collagen positive area by 65% in mice with unilateral ureteral obstruction.
Why the study?
Renal fibrosis associated with inflammation is a critical pathophysiological event in CKD, prompting investigation into the efficacy of DM509, a concurrent farnesoid X receptor agonist and soluble epoxide hydrolase inhibitor.
Does DM509 reduce renal fibrosis and inflammation in a unilateral ureteral obstruction mouse model?
Does DM509 reduce renal fibrosis and inflammation in a unilateral ureteral obstruction mouse model?
In a mouse model of chronic kidney disease, interventional treatment with the dual FXR agonist and sEH inhibitor DM509 significantly attenuated renal fibrosis, inflammation, and vascular loss.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for dual FXR/sEH inhibition in renal fibrosis; leaves open translation to human CKD.
Introduction: Renal fibrosis associated with inflammation is a critical pathophysiological event in chronic kidney disease (CKD). We have developed DM509 which acts concurrently as a farnesoid X receptor agonist and a soluble epoxide hydrolase inhibitor and investigated DM509 efficacy as an interventional treatment using the unilateral ureteral obstruction (UUO) mouse model. Methods: Male mice went through either UUO or sham surgery. Interventional DM509 treatment (10mg/kg/d) 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. Results: UUO mice demonstrated marked renal fibrosis with higher kidney hydroxyproline content and collagen positive area. Interventional DM509 treatment reduced hydroxyproline content by 41% and collagen positive area by 65%. Renal inflammation was evident in UUO mice with elevated MCP-1, CD45-positive immune cell positive infiltration, and profibrotic inflammatory gene expression. DM509 treatment reduced renal inflammation in UUO mice. Renal fibrosis in UUO was associated with epithelial-to-mesenchymal transition (EMT) and DM509 treatment reduced EMT. UUO mice also had tubular epithelial barrier injury with increased renal KIM-1, NGAL expression. DM509 reduced tubular injury markers by 25-50% and maintained tubular epithelial integrity in UUO mice. Vascular inflammation was evident in UUO mice with 9 to 20-fold higher ICAM and VCAM gene expression which was reduced by 40-50% with DM509 treatment. Peritubular vascular density was reduced by 35% in UUO mice and DM509 prevented vascular loss. Discussion: Interventional treatment with DM509 reduced renal fibrosis and inflammation in UUO mice demonstrating that DM509 is a promising drug that combats renal epithelial and vascular pathological events associated with progression of CKD.
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Khan et al. (2024) studied Renal fibrosis and inflammation (n=18). DM509 vs. Vehicle was evaluated on Renal fibrosis (hydroxyproline content and collagen positive area) (41% reduction in hydroxyproline, 65% reduction in collagen area, p=<0.05). Interventional DM509 treatment reduced kidney hydroxyproline content by 41% and collagen positive area by 65% in mice with unilateral ureteral obstruction.
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