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Biochim Biophys Acta Gen Subj. 2017 Nov;1861(11 Pt A):2758-2765. doi: 10.1016/j.bbagen.2017.07.021. Epub 2017 Jul 27.

Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia.

Author information

1
Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA 95616, United States.
2
National Institute of Environmental Health Sciences, North Carolina, NC 27709, United States.
3
Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14014 Cordoba, Spain.
4
Department of Entomology and Nematology, University of California Davis, Davis, CA 95616, United States; Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, United States.
5
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
6
Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA 95616, United States; Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, United States; Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of California Davis, Sacramento, CA 95817, United States. Electronic address: fghaj@ucdavis.edu.

Abstract

BACKGROUND:

Diabetic nephropathy (DN) is the leading cause of renal failure, and podocyte dysfunction contributes to the pathogenesis of DN. Soluble epoxide hydrolase (sEH, encoded by Ephx2) is a conserved cytosolic enzyme whose inhibition has beneficial effects on renal function. The aim of this study is to investigate the contribution of sEH in podocytes to hyperglycemia-induced renal injury.

MATERIALS AND METHODS:

Mice with podocyte-specific sEH disruption (pod-sEHKO) were generated, and alterations in kidney function were determined under normoglycemia, and high-fat diet (HFD)- and streptozotocin (STZ)-induced hyperglycemia.

RESULTS:

sEH protein expression increased in murine kidneys under HFD- and STZ-induced hyperglycemia. sEH deficiency in podocytes preserved renal function and glucose control and mitigated hyperglycemia-induced renal injury. Also, podocyte sEH deficiency was associated with attenuated hyperglycemia-induced renal endoplasmic reticulum (ER) stress, inflammation and fibrosis, and enhanced autophagy. Moreover, these effects were recapitulated in immortalized murine podocytes treated with a selective sEH pharmacological inhibitor. Furthermore, pharmacological-induced elevation of ER stress or attenuation of autophagy in immortalized podocytes mitigated the protective effects of sEH inhibition.

CONCLUSIONS:

These findings establish sEH in podocytes as a significant contributor to renal function under hyperglycemia.

GENERAL SIGNIFICANCE:

These data suggest that sEH is a potential therapeutic target for podocytopathies.

KEYWORDS:

Diabetic nephropathy; autophagy; endoplasmic reticulum stress; knockout mice; podocyte; soluble epoxide hydrolase

PMID:
28757338
PMCID:
PMC5873293
DOI:
10.1016/j.bbagen.2017.07.021
[Indexed for MEDLINE]
Free PMC Article

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