Androgen-mediated induction of the kidney arachidonate hydroxylases is associated with the development of hypertension.
Hypertension is a leading cause of cardiovascular, cerebral, and renal disease morbidity and mortality, and epidemiological evidence suggests a role for sex-dependent mechanisms in the pathophysiology of hypertension. We show here that treatment of rats with 5alpha-dihydrotestosterone increases the activity of the kidney arachidonate omega/omega-1 hydroxylase and the biosynthesis of 20-HETE (165 and 177% of control untreated male and female rats, respectively) and raises the systolic blood pressures of male and females rats by 46 and 57 mmHg, respectively. These androgen effects are associated with an upregulation in the kidney levels of CYP 4A8 mRNA and a decrease in CYP 4A1 transcripts. Dissected renal microvessels, the target tissue for most of the prohypertensive actions of 20-HETE, show an androgen-dependent upregulation of vascular CYP 4A8 mRNA and a fourfold increase in 20-HETE synthase activity. We propose that androgens regulate renal function and systemic blood pressure through a combination of transcriptional and hemodynamic mechanisms that are ultimately responsible for the regulation of renovascular tone and function.
Nakagawa
Kiyoshi
K
Departments of Medicine and Biochemistry, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA.
Marji
Jackleen S
JS
Schwartzman
Michal L
ML
Waterman
Michael R
MR
Capdevila
Jorge H
JH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013739:Testosterone / Q000097:blood
C465387:Cyp4a1protein, rat; D006893:Hydroxyeicosatetraenoic Acids; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D013739:Testosterone; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000072470:Cytochrome P450 Family 4; C409986:cytochrome P-450 omega-hydroxylase