NYMC Faculty Publications
Epoxyeicosatrienoic Acid Metabolites Inhibit Kir4.1/Kir5.1 in the Distal Convoluted tubule
DOI
10.1152/ajprenal.00018.2020
Journal Title
American Journal of Physiology. Renal Physiology
First Page
1369
Last Page
1376
Document Type
Article
Publication Date
6-1-2020
Department
Pharmacology
Keywords
8, 11, 14-Eicosatrienoic Acid, Amides, Animals, Arachidonic Acid, Cytochrome P450 Family 2, Enzyme Inhibitors, Kidney Tubules, Distal, Male, Membrane Potentials, Mice, 129 Strain, Mice, Knockout, Potassium Channel Blockers, Potassium Channels, Inwardly Rectifying
Disciplines
Medicine and Health Sciences
Abstract
Cytochrome P-450 (Cyp) epoxygenase-dependent metabolites of arachidonic acid (AA) have been shown to inhibit renal Na+ transport, and inhibition of Cyp-epoxygenase is associated with salt-sensitive hypertension. We used the patch-clamp technique to examine whether Cyp-epoxygenase-dependent AA metabolites inhibited the basolateral 40-pS K+ channel (Kir4.1/Kir5.1) in the distal convoluted tubule (DCT). Application of AA inhibited the basolateral 40-pS K+ channel in the DCT. The inhibitory effect of AA on the 40-pS K+ channel was specific because neither linoleic nor oleic acid was able to mimic the effect of AA on the K+ channel. Inhibition of Cyp-monooxygenase with N-methylsulfonyl-12,12-dibromododec-11-enamide or inhibition of cyclooxygenase with indomethacin failed to abolish the inhibitory effect of AA on the 40-pS K+ channel. However, the inhibition of Cyp-epoxygenase with N-methylsulfonyl-6-(propargyloxyphenyl)hexanamide abolished the effect of AA on the 40-pS K+ channel in the DCT. Moreover, addition of either 11,12-epoxyeicosatrienoic acid (EET) or 14,15-EET also inhibited the 40-pS K+ channel in the DCT. Whole cell recording demonstrated that application of AA decreased, whereas N-methylsulfonyl-6-(propargyloxyphenyl)hexanamide treatment increased, Ba2+-sensitive K+ currents in the DCT. Finally, application of 14,15-EET but not AA was able to inhibit the basolateral 40-pS K+ channel in the DCT of Cyp2c44-/- mice. We conclude that Cyp-epoxygenase-dependent AA metabolites inhibit the basolateral Kir4.1/Kir5.1 in the DCT and that Cyp2c44-epoxygenase plays a role in the regulation of the basolateral K+ channel in the mouse DCT.
Recommended Citation
Wang, M., Wang, L., Xiao, Y., Zhang, D., Duan, X., & Wang, W. (2020). Epoxyeicosatrienoic Acid Metabolites Inhibit Kir4.1/Kir5.1 in the Distal Convoluted tubule. American Journal of Physiology. Renal Physiology, 318 (6), 1369-1376. https://doi.org/10.1152/ajprenal.00018.2020
