Kim_2014_Am.J.Physiol.Renal.Physiol__ajprenal 00531 2014

Treating chronic kidney disease (CKD) has been challenging because of its pathogenic complexity. Epoxyeicosatrienoic acids (EETs) are cytochrome P450-dependent derivatives of arachidonic acid with anti-hypertensive, anti-inflammatory and profibrinolytic functions. We recently reported that genetic ablation of soluble epoxide hydrolase (sEH), an enzyme that converts EETs to less active dihydroxyeicosatrienoic acids, prevents renal tubulointerstitial fibrosis and inflammation in experimental mouse models of CKD. Here, we tested the hypothesis that pharmacological inhibition of sEH post-unilateral ureteral obstruction (UUO) would attenuate tubulointerstitial fibrosis and inflammation in mouse kidneys and may provide a novel approach to manage the progression of CKD. Inhibition of sEH enhanced levels of EET regioisomers and abolished tubulointerstitial fibrosis as demonstrated by reduced collagen deposition and myofibroblast formation after UUO. The inflammatory response was also attenuated as demonstrated by decreased influx of neutrophils and macrophages and decreased expression of inflammatory cytokines KC, MIP-2, MCP-1, TNF-alpha and ICAM-1 in kidneys after UUO . UUO upregulated TGF-beta1/Smad3 signaling and induced NF-kappaB activation, oxidative stress, tubular injury, apoptosis; in contrast it downregulated antifibrotic factors including peroxisome proliferators-activated receptor (PPAR) isoforms, especially PPARgamma. sEH inhibition mitigated the aforementioned malevolent effects in UUO kidneys. These data demonstrate that pharmacological inhibition of sEH promotes anti-inflammatory and fibroprotective effects in UUO kidneys by preventing tubular injury, downregulation of NF-kappaB, TGF-beta1/Smad3 and inflammatory signaling pathways and activation of PPAR isoforms. Our data suggest the potential use of sEH inhibitors in treating fibrogenesis in CKD.