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

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.

• Authors: 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
• Journal: Biochimica et biophysica acta. General subjects (Biochim Biophys Acta Gen Subj) Vol. 1861 Issue 11 Pt A Pg. 2758-2765 (Nov 2017) ISSN: 0304-4165 [Print] Netherlands
• PMID: 28757338 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Epoxide Hydrolases
• Ephx2 protein, mouse

Topics

• Animals
• Apoptosis (genetics)
• Autophagy (genetics)
• Diabetes Mellitus, Experimental (enzymology, genetics, pathology)
• Diabetic Nephropathies (enzymology, genetics, pathology)
• Endoplasmic Reticulum Stress (genetics)
• Enzyme Inhibitors (administration & dosage)
• Epoxide Hydrolases (antagonists & inhibitors, genetics)
• Humans
• Hyperglycemia (enzymology, genetics, pathology)
• Kidney (enzymology, pathology)
• Mice
• Podocytes (enzymology)