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Mechanisms of Podocyte Injury in Diabetes: Role of Cytochrome P450 and NADPH Oxidases

OBJECTIVE: We investigated the role of cytochrome P450 of the 4A family (CYP4A), its metabolites, and NADPH oxidases both in reactive oxygen species (ROS) production and apoptosis of podocytes exposed to high glucose and in OVE26 mice, a model of type 1 diabetes. RESEARCH DESIGN AND METHODS: Apoptos...

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Autores principales: Eid, Assaad A., Gorin, Yves, Fagg, Bridget M., Maalouf, Rita, Barnes, Jeffrey L., Block, Karen, Abboud, Hanna E.
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671039/
https://www.ncbi.nlm.nih.gov/pubmed/19208908
http://dx.doi.org/10.2337/db08-1536
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author Eid, Assaad A.
Gorin, Yves
Fagg, Bridget M.
Maalouf, Rita
Barnes, Jeffrey L.
Block, Karen
Abboud, Hanna E.
author_facet Eid, Assaad A.
Gorin, Yves
Fagg, Bridget M.
Maalouf, Rita
Barnes, Jeffrey L.
Block, Karen
Abboud, Hanna E.
author_sort Eid, Assaad A.
collection PubMed
description OBJECTIVE: We investigated the role of cytochrome P450 of the 4A family (CYP4A), its metabolites, and NADPH oxidases both in reactive oxygen species (ROS) production and apoptosis of podocytes exposed to high glucose and in OVE26 mice, a model of type 1 diabetes. RESEARCH DESIGN AND METHODS: Apoptosis, albuminuria, ROS generation, NADPH superoxide generation, CYP4A and Nox protein expression, and mRNA levels were measured in vitro and in vivo. RESULTS: Exposure of mouse podocytes to high glucose resulted in apoptosis, with approximately one-third of the cells being apoptotic by 72 h. High-glucose treatment increased ROS generation and was associated with sequential upregulation of CYP4A and an increase in 20-hydroxyeicosatetraenoic acid (20-HETE) and Nox oxidases. This is consistent with the observation of delayed induction of NADPH oxidase activity by high glucose. The effects of high glucose on NADPH oxidase activity, Nox proteins and mRNA expression, and apoptosis were blocked by N-hydroxy-N′-(4-butyl-2-methylphenol) formamidine (HET0016), an inhibitor of CYP4A, and were mimicked by 20-HETE. CYP4A and Nox oxidase expression was upregulated in glomeruli of type 1 diabetic OVE26 mice. Treatment of OVE26 mice with HET0016 decreased NADPH oxidase activity and Nox1 and Nox4 protein expression and ameliorated apoptosis and albuminuria. CONCLUSIONS: Generation of ROS by CYP4A monooxygenases, 20-HETE, and Nox oxidases is involved in podocyte apoptosis in vitro and in vivo. Inhibition of selected cytochrome P450 isoforms prevented podocyte apoptosis and reduced proteinuria in diabetes.
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spelling pubmed-26710392010-05-01 Mechanisms of Podocyte Injury in Diabetes: Role of Cytochrome P450 and NADPH Oxidases Eid, Assaad A. Gorin, Yves Fagg, Bridget M. Maalouf, Rita Barnes, Jeffrey L. Block, Karen Abboud, Hanna E. Diabetes Original Article OBJECTIVE: We investigated the role of cytochrome P450 of the 4A family (CYP4A), its metabolites, and NADPH oxidases both in reactive oxygen species (ROS) production and apoptosis of podocytes exposed to high glucose and in OVE26 mice, a model of type 1 diabetes. RESEARCH DESIGN AND METHODS: Apoptosis, albuminuria, ROS generation, NADPH superoxide generation, CYP4A and Nox protein expression, and mRNA levels were measured in vitro and in vivo. RESULTS: Exposure of mouse podocytes to high glucose resulted in apoptosis, with approximately one-third of the cells being apoptotic by 72 h. High-glucose treatment increased ROS generation and was associated with sequential upregulation of CYP4A and an increase in 20-hydroxyeicosatetraenoic acid (20-HETE) and Nox oxidases. This is consistent with the observation of delayed induction of NADPH oxidase activity by high glucose. The effects of high glucose on NADPH oxidase activity, Nox proteins and mRNA expression, and apoptosis were blocked by N-hydroxy-N′-(4-butyl-2-methylphenol) formamidine (HET0016), an inhibitor of CYP4A, and were mimicked by 20-HETE. CYP4A and Nox oxidase expression was upregulated in glomeruli of type 1 diabetic OVE26 mice. Treatment of OVE26 mice with HET0016 decreased NADPH oxidase activity and Nox1 and Nox4 protein expression and ameliorated apoptosis and albuminuria. CONCLUSIONS: Generation of ROS by CYP4A monooxygenases, 20-HETE, and Nox oxidases is involved in podocyte apoptosis in vitro and in vivo. Inhibition of selected cytochrome P450 isoforms prevented podocyte apoptosis and reduced proteinuria in diabetes. American Diabetes Association 2009-05 2009-02-10 /pmc/articles/PMC2671039/ /pubmed/19208908 http://dx.doi.org/10.2337/db08-1536 Text en © 2009 by the American Diabetes Association.
spellingShingle Original Article
Eid, Assaad A.
Gorin, Yves
Fagg, Bridget M.
Maalouf, Rita
Barnes, Jeffrey L.
Block, Karen
Abboud, Hanna E.
Mechanisms of Podocyte Injury in Diabetes: Role of Cytochrome P450 and NADPH Oxidases
title Mechanisms of Podocyte Injury in Diabetes: Role of Cytochrome P450 and NADPH Oxidases
title_full Mechanisms of Podocyte Injury in Diabetes: Role of Cytochrome P450 and NADPH Oxidases
title_fullStr Mechanisms of Podocyte Injury in Diabetes: Role of Cytochrome P450 and NADPH Oxidases
title_full_unstemmed Mechanisms of Podocyte Injury in Diabetes: Role of Cytochrome P450 and NADPH Oxidases
title_short Mechanisms of Podocyte Injury in Diabetes: Role of Cytochrome P450 and NADPH Oxidases
title_sort mechanisms of podocyte injury in diabetes: role of cytochrome p450 and nadph oxidases
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671039/
https://www.ncbi.nlm.nih.gov/pubmed/19208908
http://dx.doi.org/10.2337/db08-1536
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