Cytochrome P450 4F2 (CYP4F2) catalyzes the ω-hydroxylation of arachidonic acid (AA) to 20-HETE. We previously generated a CYP4F2 transgenic (TG) mouse model, and demonstrated that overexpressed CYP4F2 elevates 20-HETE production and blood pressure in the TG mice, indicating 20-HETE plays a prohypertensive role via vasoconstriction in CYP4F2 TG mice. To investigate antihypertensive action of 20-HETE via natriuresis in CYP4F2 TG mice , we fed TG mice a high salt (4% NaCl) diet for 2 weeks, and measured their systolic blood pressure (SBP), urine sodium concentration, urine volume, and urinary 20-HETE excretion. The expression of renal Na+-K+-2Cl- cotransporter, isoform 2 (NKCC2) was detected by Real-time PCR and Western blot. The results showed that SBP was not changed, but the urinary sodium excretion and urinary 20-HETE excretion were promoted by high salt intake in TG mice. NKCC2 protein was reduced by high salt intake, but its mRNA was not. These data suggest that 20-HETE of CYP4F2 TG mice exert natriuresis in renal adaptation to elevated Na+ intake, in which reduction of renal NKCC2 protein was involved through high salt-induced posttranscriptional regulation.