Role of cytochrome P450 epoxygenase in regulating renal membrane transport and hypertension

Curr Opin Nephrol Hypertens. 2013 Mar;22(2):163-9. doi: 10.1097/MNH.0b013e32835d911e.

Abstract

Purpose of review: Cytochrome P450 (CYP)-epoxygenase is highly expressed in the kidney and its metabolism of arachidonic acid plays important roles in regulating renal Na transport and in modulating vasoactivity in the kidney. In the past several years, progress has been made not only in characterizing the specific CYP-epoxygenases responsible for the regulation of membrane transport and vasoactivity in the kidney but also in exploring the mechanism by which they regulate renal Na transport and vasodilation of preglomerular arterioles. This review summarizes and updates recent progress in this area of research.

Recent findings: CYP-epoxygenase metabolites of arachidonic acid inhibit epithelial Na channel (ENaC) in the cortical collecting duct (CCD), and 11,12-epoxyeicosatrienoic acid (11,12-EET) is mainly responsible for mediating the inhibitory effect on ENaC. Downregulation of CYP2C44 abolishes arachidonic acid mediated inhibition of ENaC and increases ENaC activity. In addition, 11,12-EET stimulates Ca-activated big conductance K channels in the CCD and afferent arterioles smooth muscles. Activation of big conductance K channels by 11,12-EET is responsible for EET-induced vasodilation in preglomerular arterioles. 11,12-EET-induced vasodilation is absent in preglomerular arterioles pretreated with okadaic acid.

Summary: CYP-epoxygenase mediated suppression of renal Na transport is partially achieved by inhibition of ENaC activity in the CCD and CYP2C44-derived EETs are responsible for inhibition of ENaC. Stimulation of serine/threonine protein phosphatase 2A (PP2A) contributes to 11,12-EET-induced activation of big conductance K channels and vasodilation in preglomerular arterioles.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Arachidonic Acid / metabolism
  • Blood Pressure
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Epithelial Sodium Channels / drug effects
  • Epithelial Sodium Channels / metabolism*
  • Humans
  • Hypertension / enzymology*
  • Hypertension / genetics
  • Hypertension / physiopathology
  • Kidney / blood supply
  • Kidney / enzymology*
  • Kidney / physiopathology
  • Mice
  • Mice, Transgenic
  • Polymorphism, Genetic
  • Potassium Channels / metabolism
  • Signal Transduction
  • Sodium / metabolism
  • Vasodilation

Substances

  • Epithelial Sodium Channels
  • Potassium Channels
  • Arachidonic Acid
  • Cytochrome P-450 Enzyme System
  • Sodium
  • arachidonate epoxygenase