Disturbed ratio of renal 20-HETE/EETs is involved in androgen-induced hypertension in cytochrome P450 4F2 transgenic mice |
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Authors: | Liu Xiaoliang Wu Jingjing Liu Hong Lai Guangrui Zhao Yanyan |
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Affiliation: | Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. |
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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. |
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Keywords: | CYP4F2, cytochrome P450 4F2 AA, arachidonic acid 20-HETE, 20-hydroxyeicosatetraenoic acid KAP, kidney androgen-regulated protein EETs, epoxyeicosatrienoic acids DiHETEs, dihydroxyeicosatetraenoic acids i.p., intraperitoneally DHT, 5α-dihydrotestosterone LC-MS/MS, liquid chromatography-tandem mass spectrometry Ct, Cycle threshold values SBP, systolic blood pressure |
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