title: Disturbed ratio of renal 20-HETE/EETs is involved in androgen-induced hypertension in cytochrome P450 4F2 transgenic mice.
abstract: 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.
authors.affiliation: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Liu
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Guangrui
authors.initials: G
authors.lastname: Lai
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism* / Q000652:urine; D000728:Androgens / Q000009:adverse effects*; D000818:Animals; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism* / Q000652:urine; D006973:Hypertension / Q000139:chemically induced*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
chemical_list: C515338:11,12-epoxyeicosatrienoic acid methyl ester; D000728:Androgens; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D042926:Cytochrome P-450 CYP4A; D015126:8,11,14-Eicosatrienoic Acid