Inhibition of soluble epoxide hydrolase prevents renal interstitial fibrosis and inflammation

Abstract

The pathophysiological events that lead to renal interstitial fibrogenesis are incompletely understood. Epoxyeicosatrienoic acid (EET), an arachidonic acid metabolite, has anti-inflammatory and profibrinolytic functions. 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 deposition 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)-β1/Smad3 signaling, oxidative stress, and NF-κB activation, and downregulated antifibrotic factors including peroxisome proliferator-activated receptor (PPAR) isoforms, especially PPARγ, but the loss of sEH prevented these adverse effects in UUO kidneys. Furthermore, administration of PPAR antagonists enhanced myofibroblast formation and activation of Smad3 and NF-κB p65, effects that were prevented by sEH deficiency in UUO kidneys. These data demonstrate that loss of sEH promotes anti-inflammatory and fibroprotective effects in UUO kidneys via activation of PPAR isoforms and downregulation of NF-κB, TGF-β1/Smad3, and inflammatory signaling pathways. Our data suggest the potential use of sEH inhibitors in treating fibrotic diseases.

Keywords: PPAR isoforms; chronic kidney disease; soluble epoxide hydrolase; tubulointerstitial fibrosis; unilateral ureteral obstruction.