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Publication Detail

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

Authors: Bettaieb, Ahmed; Koike, Shinichiro; Hsu, Ming-Fo; Ito, Yoshihiro; Chahed, Samah; Bachaalany, Santana; Gruzdev, Artiom; Calvo-Rubio, Miguel; Lee, Kin Sing Stephen; Inceoglu, Bora; Imig, John D; Villalba, Jose M; Zeldin, Darryl C; Hammock, Bruce D; Haj, Fawaz G

Published In Biochim Biophys Acta Gen Subj, (2017 Nov)

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.

PubMed ID: 28757338 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis/genetics; Autophagy/genetics; Diabetes Mellitus, Experimental/enzymology; Diabetes Mellitus, Experimental/genetics*; Diabetes Mellitus, Experimental/pathology; Diabetic Nephropathies/enzymology; Diabetic Nephropathies/genetics*; Diabetic Nephropathies/pathology; Endoplasmic Reticulum Stress/genetics; Enzyme Inhibitors/administration & dosage; Epoxide Hydrolases/antagonists & inhibitors; Epoxide Hydrolases/genetics*; Humans; Hyperglycemia/enzymology; Hyperglycemia/genetics*; Hyperglycemia/pathology; Kidney/enzymology; Kidney/pathology; Mice; Podocytes/enzymology

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