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

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 Haj

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBiochimica et Biophysica Acta - General Subjects
DOIs
StateAccepted/In press - 2017

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Epoxide Hydrolases
Podocytes
Hyperglycemia
Kidney
Nutrition
Streptozocin
Fats
Enzyme inhibition
Endoplasmic Reticulum Stress
Autophagy
Diabetic Nephropathies
High Fat Diet
Pharmacology
Glucose
Wounds and Injuries
Renal Insufficiency
Proteins
Fibrosis
Inflammation
Enzymes

Keywords

  • Autophagy
  • Diabetic nephropathy
  • Endoplasmic reticulum stress
  • Knockout mice
  • Podocyte
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia. / 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.; Haj, Fawaz.

In: Biochimica et Biophysica Acta - General Subjects, 2017.

Research output: Contribution to journalArticle

Bettaieb, A, Koike, S, Hsu, MF, Ito, Y, Chahed, S, Bachaalany, S, Gruzdev, A, Calvo-Rubio, M, Lee, KSS, Inceoglu, B, Imig, JD, Villalba, JM, Zeldin, DC, Hammock, BD & Haj, F 2017, 'Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia', Biochimica et Biophysica Acta - General Subjects. https://doi.org/10.1016/j.bbagen.2017.07.021
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. ; Haj, Fawaz. / Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia. In: Biochimica et Biophysica Acta - General Subjects. 2017.
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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.",
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author = "Ahmed Bettaieb and Shinichiro Koike and Hsu, {Ming Fo} and Yoshihiro Ito and Samah Chahed and Santana Bachaalany and Artiom Gruzdev and Miguel Calvo-Rubio and Lee, {Kin Sing Stephen} and Bora Inceoglu and Imig, {John D.} and Villalba, {Jose M.} and Zeldin, {Darryl C.} and Hammock, {Bruce D.} and Fawaz Haj",
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T1 - Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia

AU - Bettaieb, Ahmed

AU - Koike, Shinichiro

AU - Hsu, Ming Fo

AU - Ito, Yoshihiro

AU - Chahed, Samah

AU - Bachaalany, Santana

AU - Gruzdev, Artiom

AU - Calvo-Rubio, Miguel

AU - Lee, Kin Sing Stephen

AU - Inceoglu, Bora

AU - Imig, John D.

AU - Villalba, Jose M.

AU - Zeldin, Darryl C.

AU - Hammock, Bruce D.

AU - Haj, Fawaz

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Autophagy

KW - Diabetic nephropathy

KW - Endoplasmic reticulum stress

KW - Knockout mice

KW - Podocyte

KW - Soluble epoxide hydrolase

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SN - 0304-4165

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