Inhibition of soluble epoxide hydrolase prevents renal interstitial fibrosis and inflammation

Jinu Kim, John D. Imig, Jun Yang, Bruce D. Hammock, Babu J. Padanilam

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

The patho-physiological events that lead to renal interstitial fibrogenesis are incompletely understood. Epoxyeicosatrienoic acid (EET), an arachi-donic acid metabolite, has anti-inflammatory and profibrinolytic func-tions. Soluble epoxide hydrolase (sEH) converts EET to less active dihydroxyeicosatrienoic acid. Here, we tested the hypothesis that sEH deficiency would prevent tubulointerstitial fibrosis and inflammation induced by unilateral ureteral obstruction (UUO) in mouse kidneys. The loss of sEH enhanced levels of EET regioisomers and abolished tubulointerstitial fibrosis as demonstrated by reduced collagen depo-sition and myofibroblast formation at 3 and 10 days after UUO. The inflammatory response was prevented as demonstrated by decreased influx of neutrophil and macrophage, expression of inflammatory cytokines, and chemotactic factors in sEH-deficient UUO kidneys. Pharmacological inhibition of sEH also prevented inflammation and fibrosis after UUO. Next, we delved into the molecular mechanisms piloting the beneficial effects of sEH deficiency in renal fibrosis. UUO upregulated profibrotic factors associated with transforming growth factor (TGF)-1/Smad3 signaling, oxidative stress, and NF-B acti-vation, and downregulated antifibrotic factors including peroxisome proliferator-activated receptor (PPAR) isoforms, especially PPAR, but the loss of sEH prevented these adverse effects in UUO kidneys. Furthermore, administration of PPAR antagonists enhanced myofi-broblast formation and activation of Smad3 and NF-B p65, effects that were prevented by sEH deficiency in UUO kidneys. These data demonstrate that loss of sEH promotes anti-inflammatory and fibro-protective effects in UUO kidneys via activation of PPAR isoforms and downregulation of NF-B, TGF-1/Smad3, and inflammatory signaling pathways. Our data suggest the potential use of sEH inhib-itors in treating fibrotic diseases.

Original languageEnglish (US)
Pages (from-to)F971-F980
JournalAmerican Journal of Physiology - Renal Physiology
Volume307
Issue number8
DOIs
StatePublished - Oct 15 2014
Externally publishedYes

Keywords

  • Chronic kidney disease
  • PPAR isoforms
  • Soluble epoxide hydrolase
  • Tubulointerstitial fibrosis
  • Unilateral ureteral obstruction

ASJC Scopus subject areas

  • Physiology
  • Urology
  • Medicine(all)

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