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The aim of this study is to test whether the Cyp2c44 epoxygenase-dependent metabolism of arachidonic acid prevents the hypertensive effect of a high K (HK) intake by inhibiting the epithelial sodium channel (ENaC) activity. A HK intake elevated Cyp2c44 mRNA expression and 11,12-epoxyeicosatrienoic acid levels in the cortical collecting duct inCyp2c44(+/+) mice (wild-type [wt]). However, an HK intake failed to increase 11,12-epoxyeicosatrienoic acid formation in the cortical collecting ducts ofCyp2c44(−/−) mice. Moreover, increasing K intake enhanced arachidonic acid–induced inhibition of ENaC in the wt but not inCyp2c44(−/−) mice. In contrast, 11,12-epoxyeicosatrienoic acid, a Cyp2c44 metabolite, inhibited ENaC in the wt andCyp2c44(−/−) mice. The notion that Cyp2c44 is the epoxygenase responsible for mediating the inhibitory effects of arachidonic acid on ENaC is further suggested by the observation that inhibiting Cyp-epoxygenase increased the whole-cell Na currents in principal cells of wt but not inCyp2c44(−/−) mice. Feeding mice with an HK diet raised the systemic blood pressures ofCyp2c44(−/−) mice but was without an effect on wt mice. Moreover, application of amiloride abolished the HK-induced hypertension inCyp2c44(−/−) mice. The HK-induced hypertension ofCyp2c44(−/−) mice was accompanied by decreasing 24-hour urinary Na excretion and increasing the plasma Na concentration, and the effects were absent in wt mice. In contrast, disruption of theCyp2c44 gene did not alter K excretion. We conclude that Cyp2c44 epoxygenase mediates the inhibitory effect of arachidonic acid on ENaC and that Cyp2c44 functions as an HK-inducible antihypertensive enzyme responsible for inhibiting ENaC activity and Na absorption in the aldosterone-sensitive distal nephron.

Cyp2c44 Epoxygenase Is Essential for Preventing the Renal Sodium Absorption During Increasing Dietary Potassium Intake