Pharmacological inhibition of soluble epoxide hydrolase prevents renal interstitial fibrogenesis in obstructive nephropathy

Jinu Kim, Sang Pil Yoon, Myron L. Toews, John D. Imig, Sung Hee Hwang, Bruce D. Hammock, Babu J. Padanilam

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Treating chronic kidney disease (CKD) has been challenging because of its pathogenic complexity. Epoxyeicosatrienoic acids (EETs) are cytochrome P-450-dependent derivatives of arachidonic acid with antihypertensive, 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 after 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 keratinocyte chemoattractant, macrophage inflammatory protein-2, monocyte chemotactic protein-1, TNF-α, and ICAM-1 in kidneys after UUO. UUO upregulated transforming growth factor-β<inf>1</inf>/Smad3 signaling and induced NF-κB activation, oxidative stress, tubular injury, and apoptosis; in contrast, it downregulated antifibrotic factors, including peroxisome proliferator-activated receptor (PPAR) isoforms, especially PPAR-γ. 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-κB, transforming growth factor-β<inf>1</inf>/Smad3, and inflammatory signaling pathways, and activation of PPAR isoforms. Our data suggest the potential use of sEH inhibitors in treating fibrogenesis in the UUO model of CKD.

Original languageEnglish (US)
Pages (from-to)F131-F139
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number1
DOIs
StatePublished - 2015

Fingerprint

Epoxide Hydrolases
Ureteral Obstruction
Pharmacology
Kidney
Chronic Renal Insufficiency
Peroxisome Proliferator-Activated Receptors
Fibrosis
Transforming Growth Factors
Protein Isoforms
Anti-Inflammatory Agents
Down-Regulation
Chemokine CXCL2
Inflammation
Acids
Myofibroblasts
Chemokine CCL2
Chemotactic Factors
Wounds and Injuries
Intercellular Adhesion Molecule-1
Keratinocytes

Keywords

  • Chronic kidney disease
  • Epoxyeicosatrienoic acid
  • Peroxisome prolif-erator-activated receptor
  • Soluble epoxide hydrolase
  • Trans-4-{4-[3-(4-trifluoromethoxyphenyl)ureido]cyclohexyloxy} benzoic acid

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Pharmacological inhibition of soluble epoxide hydrolase prevents renal interstitial fibrogenesis in obstructive nephropathy. / Kim, Jinu; Yoon, Sang Pil; Toews, Myron L.; Imig, John D.; Hwang, Sung Hee; Hammock, Bruce D.; Padanilam, Babu J.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 308, No. 1, 2015, p. F131-F139.

Research output: Contribution to journalArticle

Kim, Jinu ; Yoon, Sang Pil ; Toews, Myron L. ; Imig, John D. ; Hwang, Sung Hee ; Hammock, Bruce D. ; Padanilam, Babu J. / Pharmacological inhibition of soluble epoxide hydrolase prevents renal interstitial fibrogenesis in obstructive nephropathy. In: American Journal of Physiology - Heart and Circulatory Physiology. 2015 ; Vol. 308, No. 1. pp. F131-F139.
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