Proximal tubular-targeted overexpression of the Cyp4a12-20-HETE synthase promotes salt-sensitive hypertension in male mice.

20-Hydroxyeicosatetraenoic acid (20-HETE) has been linked to blood pressure (BP) regulation via actions on the renal microvasculature and tubules. We assessed tubular 20-HETE contribution to hypertension by generating transgenic mice overexpressing the CYP4A12-20-HETE synthase (PT-4a12 mice) under the control of the proximal tubule (PT)-specific promoter, phosphoenolpyruvate carboxykinase (PEPCK). 20-HETE levels in the kidney cortex of male (967±210 vs. 249±69 pg/mg protein), but not female (121±15 vs. 92±11 pg/mg protein) PT-4a12 mice, showed a 2.5-fold increase compared to WT. Renal cortical Cyp4a12 mRNA and CYP4A12 protein in male, but not female PT-4a12 mice increased by 2-3-fold compared to WT. Male PT-4a12 mice displayed elevated BP (142±1 vs. 111±4 mmHg, p<0.0001), whereas BP in females PT-4a12 mice was not significantly different from WT (118±2 vs. 117±2 mmHg; p=0.98). In male PT-4a12 mice, BP decreased when transitioned from a control salt (0.4%) to a low-salt diet (0.075%) from 135±4 to 120±6 mmHg (p<0.01) and increased to 153±5 mmHg (p<0.05) when placed on a high-salt diet (4%). Female PT-4a12 mice did not show changes in BP on either low- or high-salt diet. In conclusion, the expression of Cyp4a12 driven by the PEPCK promoter is sex-specific probably due to its X-linkage. The salt-sensitive hypertension seen in PT-4a12 male mice suggests a potential anti-natriuretic activity of 20-HETE that needs to be further explored.