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

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.

Fig. 1

Reactions catalyzed by cytochrome P450 during arachidonic acid metabolism

Fig. 2

A cell scheme illustrating the role of CYP2C44 in regulation of Na transport in the CCD. The inhibitory effect of 11,12-EET on ENaC is achieved by blocking apical ENaC and basolateral K channels. In addition, 11,12-EET mediates the adenosine-induced inhibition of ENaC.

Fig. 3

A scheme illustrating the mechanism by which 11,12-EET activates the BK channels in smooth muscles of afferent arterioles. Asterisk represents 59 amino acid insertion (STREX) in the alpha subunit of the BK channels.

Fig. 4

A scheme illustrating the role of CYP-epoxygenase-dependent AA metabolism in suppressing ENaC and in preventing excessive Na absorption in the CCD when dietary K intake increases. Solid line arrow and dotted line arrow represent a stimulation and an inhibition, respectively.