Inhibition of soluble epoxide hydrolase attenuates renal tubular mitochondrial dysfunction and ER stress by restoring autophagic flux in diabetic nephropathy

• Published in: Cell death & disease 2020-05, Vol.11 (5), p.385-385, Article 385
• Main Authors: Jiang, Xu-shun, Xiang, Xing-yang, Chen, Xue-mei, He, Jun-ling, Liu, Ting, Gan, Hua, Du, Xiao-gang
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 13/31; 14/28; 14/34; 14/35; 38/109; 631/337; 692/699/1585/104; 82/29; 96/95; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; BAX protein; Biochemistry; Biological activity; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cytochrome c; Cytoplasm; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Diabetic nephropathy; End-stage renal disease; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; Epoxide hydrolase; Epoxide Hydrolases - genetics; Epoxide Hydrolases - pharmacology; Fatty acids; Humans; Hyperglycemia; Hyperglycemia - drug therapy; Hyperglycemia - pathology; Immunology; Kidney - pathology; Kidney diseases; Life Sciences; Metabolites; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Nephropathy; Pathogenesis; Phagocytosis; Reactive oxygen species; Renal function; Staphylococcal enterotoxin H
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2594-x

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD), and renal tubular cell dysfunction contributes to the pathogenesis of DN. Soluble epoxide hydrolase (sEH) is an enzyme that can hydrolyze epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs) into the less biologically active metabolites. Inhibition of sEH has multiple beneficial effects on renal function, however, the exact role of sEH in hyperglycemia-induced dysfunction of tubular cells is still not fully elucidated. In the present study, we showed that human proximal tubular epithelial (HK-2) cells revealed an upregulation of sEH expression accompanied by the impairment of autophagic flux, mitochondrial dysfunction, ubiquitinated protein accumulation and enhanced endoplasmic reticulum (ER) stress after high glucose (HG) treatment. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which resulted in excessive reactive oxygen species (ROS) generation, Bax translocation, cytochrome c release, and apoptosis. However, t -AUCB, an inhibitor of sEH, partially reversed these negative outcomes. Moreover, we also observed increased sEH expression, impaired autophagy flux, mitochondrial dysfunction and enhanced ER stress in the renal proximal tubular cells of db/db diabetic mice. Notably, inhibition of sEH by treatment with t -AUCB attenuated renal injury and partially restored autophagic flux, improved mitochondrial function, and reduced ROS generation and ER stress in the kidneys of db/db mice. Taken together, these results suggest that inhibition of sEH by t -AUCB plays a protective role in hyperglycemia-induced proximal tubular injury and that the potential mechanism of t -AUCB-mediated protective autophagy is involved in modulating mitochondrial function and ER stress. Thus, we provide new evidence linking sEH to the autophagic response during proximal tubular injury in the pathogenesis of DN and suggest that inhibition of sEH can be considered a potential therapeutic strategy for the amelioration of DN.