Disturbed ratio of renal 20-HETE/EETs is involved in androgen-induced hypertension in cytochrome P450 4F2 transgenic mice

We have previously established a cytochrome P450 4F2 (CYP4F2) transgenic mouse model. The present study elucidated the molecular foundation of hypertension by androgen-induction in this model. The renal expression of CYP4F2 in transgenic mice was highly expressed and strongly induced with 5α-dihydrotestosterone (DHT) treatment determined by Western blot. DHT also increased the renal arachidonic acid ω-hydroxylation and urinary 20-hydroxyeicosatetraenoic acid (20-HETE) excretion (P < 0.01), and furthermore elevated the systolic blood pressure by 10 and 22 mm Hg (P < 0.05) in female and castrated male transgenic mice, respectively. HET0016 completely eliminated the androgen-induced effects (P < 0.01). Endogenous Cyp4a ω-hydroxylases, evaluated by real-time quantitative PCR, were significantly suppressed in transgenic mice (P < 0.05). Importantly, transgenic mice with increased 20-HETE showed decreased epoxyeicosatrienoic acids (EETs) and increased dihydroxyeicosatetraenoic acids determined by liquid chromatography-tandem mass spectrometry, contributing to significantly raised ratio of 20-HETE/EETs in the urine and kidney homogenate (P < 0.01). These data demonstrate that the androgen aggravated hypertension possibly through an altered ratio of 20-HETE/EETs in CYP4F2 transgenic mice.

► We applied androgen induction on CYP4F2 transgenic mice.
► Androgen induces CYP4F2 expression and activity and enhanced 20-HETE production.
► Androgen-induction on CYP4F2/20-HETE aggravated hypertension.
► Increased 20-HETE was accompanied with altered EETs and DiHETEs.
► The disturbed ratio of 20-HETE/EETs might be a molecular foundation of hypertension.