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

Biochimica et biophysica acta. General subjects 2017 Nov

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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. 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. 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. These findings establish sEH in podocytes as a significant contributor to renal function under hyperglycemia. These data suggest that sEH is a potential therapeutic target for podocytopathies. Copyright © 2017 Elsevier B.V. All rights reserved.

Citation

Ahmed Bettaieb, Shinichiro Koike, Ming-Fo Hsu, Yoshihiro Ito, Samah Chahed, Santana Bachaalany, Artiom Gruzdev, Miguel Calvo-Rubio, Kin Sing Stephen Lee, Bora Inceoglu, John D Imig, Jose M Villalba, Darryl C Zeldin, Bruce D Hammock, Fawaz G Haj. Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia. Biochimica et biophysica acta. General subjects. 2017 Nov;1861(11 Pt A):2758-2765