期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1861, 期 11, 页码 2758-2765出版社
ELSEVIER
DOI: 10.1016/j.bbagen.2017.07.021
关键词
Diabetic nephropathy; soluble epoxide hydrolase; podocyte; knockout mice; autophagy; endoplasmic reticulum stress
资金
- National Institutes of Health [R01DK090492, R01DK095359, K99DK100736, R00DK100736, DK103616, R01ES002710, R01DK103616]
- NIH/NIDDK [U24DK092993]
- Spanish Ministerio de Economia y Competitividad [BFU2011-23578, BFU2015-64630-R]
- Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A.
- NIH, National Institute of Environmental Health Sciences [Z01 E5025034]
- National Institute of Environmental Health Sciences [P42 ES04699]
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.
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