Journal
PROSTAGLANDINS & OTHER LIPID MEDIATORS
Volume 150, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.prostaglandins.2020.106472
Keywords
Renal fibrosis; Bifunctional drug; PPAR-gamma agonist; Soluble epoxide hydrolase inhibitor
Categories
Funding
- National Institute of Health (NIH) [DK103616]
- Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee grant
- Deutsche Forschungsgemeinschaft (Heisenberg) [PR 1405/4-1, SFB 1039]
- Else-Kroner-Fresenius Foundation graduate college for Translational Research Innovation - Pharma (TRIP)
- German Cancer Consortium (DKTK)
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Renal fibrosis is a contributor to chronic kidney disease and an important predictor of long-term prognosis. We developed a dual soluble epoxide hydrolase inhibitor-PPAR-gamma agonist (sEHi/PPAR-gamma), RB394, and investigated its ability to attenuate renal fibrosis in a mouse unilateral ureteral obstruction (UUO) model. RB394 efficacy was compared to an sEH inhibitor (sEHi), a PPAR-gamma agonist rosiglitazone (Rosi), or their combination (sEHi + Rosi). All interventional treatments were administrated in drinking water 3 days after UUO induction surgery and continued for 7 days. UUO mice developed renal fibrosis with higher collagen formation and RB394 significantly attenuated fibrosis (P < 0.05). Renal expression of alpha-smooth muscle actin (alpha-SMA) was elevated in UUO mice and all treatments except sEHi significantly attenuated renal alpha-SMA expression. Renal mRNA expression fibrotic and fibrosis regulators were higher in UUO mice and RB394 and sEHi + Rosi treatments attenuated their expression. Renal inflammation was evident in UUO mice with increased infiltration of CD45 and F4/80 positive cells. RB394 and sEHi + Rosi treatments attenuated renal inflammation in UUO mice. UUO mice had renal tubular and vascular injury. Renal tubular and vascular injuries were attenuated to a greater extent by RB394 and sEHi + Rosi than sEHi or Rosi treatment alone. Renal mRNA expression of oxidative stress markers were significantly higher in UUO mice (P < 0.05). RB394 and sEHi + Rosi attenuated expression of oxidative stress markers to a greater extent than other interventional treatments (P < 0.05). These findings demonstrate that RB394 can attenuate renal fibrosis by reducing renal inflammation, oxidative stress, tubular injury, and vascular injury. In conclusion, RB394 demonstrates exciting potential as a therapeutic for renal fibrosis and chronic kidney disease.
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