Epoxyeicosatrienoic acid metabolites inhibit Kir4.1/Kir5.1 in the distal convoluted tubule
Epoxyeicosatrienoic acid metabolites inhibit Kir4.1/Kir5.1 in the distal convoluted tubule
复制标题
环氧二十碳三烯酸代谢物抑制远曲小管中的 Kir4.1/Kir5.1
DOI：
10.1152/ajprenal.00018.2020
复制
发表时间：
2020
影响因子：
4.2
通讯作者：
Wang Wen-Hui
中科院分区：
文献类型：
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作者：
Wang Ming-Xiao;Wang Li-Jun;Xiao Yu;Zhang Dan-Dan;Duan Xin-Peng;Wang Wen-Hui
花生四烯酸(AA)依赖细胞色素P-450(Cyp)环氧合酶的代谢产物可抑制肾脏Na+转运，环氧合酶抑制与盐敏感型高血压有关。我们用膜片钳技术检测环氧合酶依赖的AA代谢物是否抑制远端曲管(DCT)的40-pS K+通道(Kir4.1/Kir5.1)。AA可抑制DCT的基底外侧40-pS K+通道。AA对40-PS K+通道的抑制作用是特异的，因为亚油酸和油酸都不能模拟AA对K+通道的作用。抑制环氧合酶withN-methylsulfonyl-12，12-dibromododec-11-enamide或用消炎痛抑制环氧合酶均不能消除AA对40-pS K+通道的抑制作用。然而，环氧合酶withN-methylsulfonyl-6-(propargyloxyphenyl)hexanamide的抑制取消了AA对DCT中40-pS钾通道的作用。此外，加入11，12-环氧二十碳三烯酸(EET)或14，15-EET也可抑制DCT的40-pS K+通道。全细胞记录显示AA应用减少，whereasN-methylsulfonyl-6-(propargyloxyphenyl)hexanamide处理增加，DCT中Ba2+敏感的K+电流增加。最后，应用14，15-EET而不是AA能够抑制Cyp2c44−/−小鼠DCT的基底外侧40-pS K+通道。我们的结论是，环氧合酶依赖的AA代谢物抑制了DCT中的基底侧Kir4.1/Kir5.1，而Cyp2c44-环氧合酶在调节小鼠DCT中的基底侧K+通道中起作用。
CytochromeP-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 withN-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 withN-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, whereasN-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 ofCyp2c44−/−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.