1. Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia
- Author
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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, and Haj, Fawaz G
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Kidney Disease ,Nutrition ,Diabetes ,Aetiology ,2.1 Biological and endogenous factors ,Renal and urogenital ,Animals ,Apoptosis ,Autophagy ,Diabetes Mellitus ,Experimental ,Diabetic Nephropathies ,Endoplasmic Reticulum Stress ,Enzyme Inhibitors ,Epoxide Hydrolases ,Humans ,Hyperglycemia ,Kidney ,Mice ,Podocytes ,Diabetic nephropathy ,soluble epoxide hydrolase ,podocyte ,knockout mice ,autophagy ,endoplasmic reticulum stress ,Pharmacology and Pharmaceutical Sciences ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
BackgroundDiabetic 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 methodsMice 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.ResultssEH 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.ConclusionsThese findings establish sEH in podocytes as a significant contributor to renal function under hyperglycemia.General significanceThese data suggest that sEH is a potential therapeutic target for podocytopathies.
- Published
- 2017