Ahmed Bettaieb1, Shinichiro Koike1, Ming-Fo Hsu1, Yoshihiro Ito1, Samah Chahed1, Santana Bachaalany1, Artiom Gruzdev2, Miguel Calvo-Rubio3, Kin Sing Stephen Lee4, Bora Inceoglu4, John D Imig5, Jose M Villalba3, Darryl C Zeldin2, Bruce D Hammock4, Fawaz G Haj6. 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.
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.
Authors: Z Yu; F Xu; L M Huse; C Morisseau; A J Draper; J W Newman; C Parker; L Graham; M M Engler; B D Hammock; D C Zeldin; D L Kroetz Journal: Circ Res Date: 2000-11-24 Impact factor: 17.367
Authors: John D Imig; Xueying Zhao; Constantine Z Zaharis; Jeffrey J Olearczyk; David M Pollock; John W Newman; In-Hae Kim; Takaho Watanabe; Bruce D Hammock Journal: Hypertension Date: 2005-09-12 Impact factor: 10.190
Authors: Lu Liu; Nitin Puri; Marco Raffaele; Joseph Schragenheim; Shailendra P Singh; J Alyce Bradbury; Lars Bellner; Luca Vanella; Darryl C Zeldin; Jian Cao; Nader G Abraham Journal: Prostaglandins Other Lipid Mediat Date: 2018-07-21 Impact factor: 3.072
Authors: Marianne K O Grant; Davis M Seelig; Leslie C Sharkey; Wan S V Choi; Ibrahim Y Abdelgawad; Beshay N Zordoky Journal: PLoS One Date: 2019-02-20 Impact factor: 3.240
Authors: Haley Overby; Yang Yang; Xinyun Xu; Katherine Graham; Kelsey Hildreth; Sue Choi; Debin Wan; Christophe Morisseau; Darryl C Zeldin; Bruce D Hammock; Shu Wang; Ahmed Bettaieb; Ling Zhao Journal: Int J Mol Sci Date: 2020-09-24 Impact factor: 5.923