Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury
Authors: James Graham
Artiom Gruzdev
Bruce D Hammock
Huma Fatima
Ahmed Bettaieb
Peter J Havel
Santana Bachaalany
Nader Hashoush
Yi Zhao
Fawaz G Haj
Samah Chahed
Shinichiro Koike
Darryl C Zeldin
Journal: FEBS Journal (2017)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: knockout mice; podocyte; proteinuria; soluble epoxide hydrolase.
Affiliations: Department of Nutrition, University of California Davis, CA, USA., Department of Nutrition, University of Tennessee-Knoxville, TN, USA., Department of Pathology, University of Alabama at Birmingham, AL, USA., Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, CA, USA., Division of Intramural Research, National Institute of Environmental Health Sciences, Durham, NC, USA., Department of Entomology and Nematology, University of California Davis, CA, USA., Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA., Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA.

Abstract:  Podocytes play an important role in maintaining glomerular function, and podocyte injury is a significant component in the pathogenesis of proteinuria. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose genetic deficiency and pharmacological inhibition have beneficial effects on renal function, but its role in podocytes remains unexplored. The objective of this study was to investigate the contribution of sEH in podocytes to lipopolysaccharide (LPS)-induced kidney injury. We report increased sEH transcript and protein expression in murine podocytes upon LPS challenge. To determine the function of sEH in podocytes in vivo we generated podocyte-specific sEH-deficient (pod-sEHKO) mice. Following LPS challenge, podocyte sEH-deficient mice exhibited lower kidney injury, proteinuria, and blood urea nitrogen concentrations than controls suggestive of preserved renal function. Also, renal mRNA and serum concentrations of inflammatory cytokines IL-6, IL-1β, and TNFα were significantly lower in LPS-treated pod-sEHKO than control mice. Moreover, podocyte sEH deficiency was associated with decreased LPS-induced NF-κB and MAPK activation and attenuated endoplasmic reticulum stress. Furthermore, the protective effects of podocyte sEH deficiency in vivo were recapitulated in E11 murine podocytes treated with a selective sEH pharmacological inhibitor. Altogether, these findings identify sEH in podocytes as a contributor to signaling events in acute renal injury and suggest that sEH inhibition may be of therapeutic value in proteinuria. Enzymes: Soluble epoxide hydrolase: EC 3.3.2.10. 

Retracted: No

PubPeer comments:
 Corrigendum, 2018: https: febs.onlinelibrary.wiley.com doi 10.1111 febs.14361  In the paper by Bettaieb et al. [1], we were alerted to the presence of duplicated bands in several figures. Specifically, the IKKu03b1 and Tubulin bands in Fig. 4C were identical, as were the eIF2u03b1 and IRE1 bands in Fig. 5 and the NF-u03baBp65 and Tubulin bands in Fig. 6A. Table 1 also contained inadvertent typographical errors. Here is the original Figure 4C, with the duplication marked with red boxes: ![file] Here is the original Figure 5, with the duplication marked with blue boxes: ![file] Here is the original Figure 6A, with the duplication marked with teal boxes: ![file] ,