Overexpression of cytochrome P450 4F2 in mice increases 20-hydroxyeicosatetraenoic acid production and arterial blood pressure

Abstract

Cytochrome P450 4F2 (CYP4F2) activity is thought to be a factor in the pathogenesis of hypertension through its bioactive metabolite 20-hydroxyeicosatetraenoic acid (20-HETE). We previously found that a gain-in-function CYP4F2 variant in a Chinese cohort was associated with elevated urinary 20-HETE and hypertension. To further explore this association we generated a transgenic mouse model expressing CYP4F2 driven by a modified mouse kidney androgen-regulated protein promoter. This heterologous promoter regulated the expression of luciferase and his-tagged CYP4F2 in transfected HEK 293 cells. In the kidney of transgenic mice, CYP4F2 was localized to renal proximal tubule epithelia and was expressed at a higher level than in control mice, leading to increased urinary 20-HETE excretion. Assessment of CYP4F2 activity by an arachidonic acid hydroxylation assay showed that 20-HETE production was significantly higher in kidney microsomes of transgenic mice compared to control mice, as was their systolic blood pressure. There was a positive correlation of blood pressure with urinary 20-HETE levels. Our results show that increased expression of CYP4F2 in mice enhanced 20-HETE production and elevated blood pressure.