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Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia. Biochim Biophys Acta Gen Subj 2017 Nov;1861(11 Pt A):2758-2765

Date

08/02/2017

Pubmed ID

28757338

Pubmed Central ID

PMC5873293

DOI

10.1016/j.bbagen.2017.07.021

Scopus ID

2-s2.0-85026839067 (requires institutional sign-in at Scopus site)   23 Citations

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.

Author List

Bettaieb A, Koike S, Hsu MF, Ito Y, Chahed S, Bachaalany S, Gruzdev A, Calvo-Rubio M, Lee KSS, Inceoglu B, Imig JD, Villalba JM, Zeldin DC, Hammock BD, Haj FG

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Autophagy
Diabetes Mellitus, Experimental
Diabetic Nephropathies
Endoplasmic Reticulum Stress
Enzyme Inhibitors
Epoxide Hydrolases
Humans
Hyperglycemia
Kidney
Mice
Podocytes