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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Stavniichuk A, Hye Khan MA, Yeboah MM, Chesnik MA, Jankiewicz WK, Hartmann M, Blocher R, Kircher T, Savchuk O, Proschak E, Imig JD (2020) Dual Soluble Epoxide Hydrolase Inhibitor/PPAR-gamma Agonist Attenuates Renal Fibrosis Prostaglandins Other Lipid Mediat
Stavniichuk A, Hye Khan MA, Yeboah MM, Chesnik MA, Jankiewicz WK, Hartmann M, Blocher R, Kircher T, Savchuk O, Proschak E, Imig JD (2020) Prostaglandins Other Lipid Mediat