Pharmacological inhibition of soluble epoxide hydrolase prevents renal interstitial fibrogenesis in obstructive nephropathy.
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-β1/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-β1/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.
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; Department of Anatomy, Jeju National University School of Medicine, Jeju, Republic of Korea; Department of Biomedicine and Drug Development, Jeju National University, Jeju, Republic of Korea;
Jinu
J
Kim
Department of Anatomy, Jeju National University School of Medicine, Jeju, Republic of Korea;
Sang Pil
SP
Yoon
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska;
Myron L
ML
Toews
Department of Pharmacology and Toxicology and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin;
John D
JD
Imig
Department of Entomology and Comprehensive Cancer Center, University of California, Davis, California; and.
Sung Hee
SH
Hwang
Department of Entomology and Comprehensive Cancer Center, University of California, Davis, California; and.
Bruce D
BD
Hammock
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; Department of Internal Medicine, Section of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska bpadanilam@unmc.edu.
Babu J
BJ
Padanilam
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D008297:Male; D008810:Mice, Inbred C57BL; D009400:Nephrosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D012079:Renal Circulation / Q000187:drug effects; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014517:Ureteral Obstruction / Q000150:complications
C572961:4-(4-(3-(4-trifluoromethoxy-phenyl)ureido)cyclohexyloxy)benzoic acid; D001095:Arachidonic Acids; D001565:Benzoates; D047492:Peroxisome Proliferator-Activated Receptors; D010671:Phenylurea Compounds; D004851:Epoxide Hydrolases
chronic kidney disease; epoxyeicosatrienoic acid; peroxisome proliferator-activated receptor; soluble epoxide hydrolase; trans-4-{4-[3-(4-trifluoromethoxyphenyl)ureido]cyclohexyloxy}benzoic acid