Overexpression of cytochrome P450 4F2 in mice increases 20-hydroxyeicosatetraenoic acid production and arterial blood pressure.
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.
Liu
Xiaoliang
X
Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
Zhao
Yanyan
Y
Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China. Electronic address: yyzhao@mail.cmu.edu.cn.
Wang
Luzeng
L
Department of Laboratory Animal Center, China Medical University, Shenyang, Liaoning, China.
Yang
Xianghong
X
Department of Pathology, the Second Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
Zheng
Zhihong
Z
Department of Laboratory Animal Center, China Medical University, Shenyang, Liaoning, China.
Zhang
Yuanyuan
Y
Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
Chen
Fangjie
F
Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
Liu
Hong
H
Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis* / Q000652:urine; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D018076:DNA, Complementary; D006893:Hydroxyeicosatetraenoic Acids; D011994:Recombinant Proteins; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human