Involvement of renal cytochromes P450 and arachidonic acid metabolites in diabetic nephropathy

S. Eid, W. Abou-Kheir, R. Sabra, G. Daoud, A. Jaffa, F. N. Ziyadeh, L. Roman, Assaad A. Eid

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Diabetic nephropathy (DN) is one of the most serious complications of type I and type II diabetes. DN is characterized by hyperfiltration, hypertrophy, extracellular matrix accumulation, and proteinuria. This advances into renal fibrosis and loss of renal function. Reactive oxygen species (ROS) and TGF-β have been implicated in the pathogenesis of diabetic nephropathy. Early stages of diabetic nephropathy are also associated with alterations in renal sodium handling as well as hypertension; both are processes linked by involvement of the arachidonic acid (AA) metabolites, 20-hydroxyeicosatetraenoic acid (20-HETE, produced by cytochrome P450-4a, (CYP4A) and epoxyeicosatrienoic acids (EETs). Indeed, metabolism of AA is increased in a rat model of diabetes. In this study, we demonstrate that rats with streptozotocin-induced diabetes of 1 month duration develop renal hypertrophy and increased fibronectin and TGF-β1 expression/cortical levels concomitant with an increase in CYP4A expression and 20 HETE production. These results were also paralleled by an increase in reactive oxygen species (ROS) production and NADPH oxidase activity. Treatment of diabetic rats with HET0016, selective inhibitor of CYP4A, prevented all these changes. Our results suggest that diabetes-induced induction of CYP4A and 20-HETE production could be a major pathophysiological mechanism leading to activation of ROS through an NADPH dependent pathway and TGF-β1 thus resulting in major renal pathology. Inhibitors of 20-HETE production could thus have an important therapeutic potential in the treatment of diabetic nephropathy.

Original languageEnglish (US)
Pages (from-to)693-703
Number of pages11
JournalJournal of Biological Regulators and Homeostatic Agents
Volume27
Issue number3
StatePublished - 2013

Keywords

  • 20-HETE
  • Cytochromes P450
  • Diabetic nephropathy
  • NADPH oxidase
  • Reactive oxygen species
  • TGF-β

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Immunology and Allergy
  • Physiology
  • Immunology
  • Oncology
  • Endocrinology
  • Physiology (medical)
  • Cancer Research

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  • Cite this

    Eid, S., Abou-Kheir, W., Sabra, R., Daoud, G., Jaffa, A., Ziyadeh, F. N., Roman, L., & Eid, A. A. (2013). Involvement of renal cytochromes P450 and arachidonic acid metabolites in diabetic nephropathy. Journal of Biological Regulators and Homeostatic Agents, 27(3), 693-703.