Dual soluble epoxide hydrolase inhibitor/PPAR-γ agonist attenuates renal fibrosis.

Autor: Stavniichuk A; Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA; Educational & Scientific Center, Institute of Biology and Medicine, Taras Shevchenko National University, Kyiv, Ukraine., Hye Khan MA; Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: abhkhan@mcw.edu., Yeboah MM; Nephrology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA., Chesnik MA; Nephrology Division, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA., Jankiewicz WK; Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA., Hartmann M; Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Frankfurt am Main, Germany., Blöcher R; Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Frankfurt am Main, Germany., Kircher T; Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Frankfurt am Main, Germany., Savchuk O; Educational & Scientific Center, Institute of Biology and Medicine, Taras Shevchenko National University, Kyiv, Ukraine., Proschak E; Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Frankfurt am Main, Germany., Imig JD; Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Jazyk: angličtina
Zdroj: Prostaglandins & other lipid mediators [Prostaglandins Other Lipid Mediat] 2020 Oct; Vol. 150, pp. 106472. Date of Electronic Publication: 2020 Jun 20.
DOI: 10.1016/j.prostaglandins.2020.106472
Abstrakt: 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-γ agonist (sEHi/PPAR-γ), 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-γ 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 α-smooth muscle actin (α-SMA) was elevated in UUO mice and all treatments except sEHi significantly attenuated renal α-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.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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