20-Hydroxyeicosatetraenoic Acid (HETE)-dependent Hypertension in Human Cytochrome P450 (CYP) 4A11 Transgenic Mice: NORMALIZATION OF BLOOD PRESSURE BY SODIUM RESTRICTION, HYDROCHLOROTHIAZIDE, OR BLOCKADE OF THE TYPE 1 ANGIOTENSIN II RECEPTOR.
Male and female homozygous 129/Sv mice carrying four copies of the human cytochrome P450 4A11 gene (CYP4A11) under control of its native promoter (B-129/Sv-4A11(+/+)) develop hypertension (142 ± 8 versus 113 ± 7 mm Hg systolic blood pressure (BP)), and exhibit increased 20-hydroxyeicosatetraenoic acid (20-HETE) in kidney and urine. The hypertension is reversible by a low-sodium diet and by the CYP4A inhibitor HET0016. B-129/Sv-4A11(+/+) mice display an 18% increase of plasma potassium (p < 0.02), but plasma aldosterone, angiotensin II (ANGII), and renin activities are unchanged. This phenotype resembles human genetic disorders with elevated activity of the sodium chloride co-transporter (NCC) and, accordingly, NCC abundance is increased by 50% in transgenic mice, and NCC levels are normalized by HET0016. ANGII is known to increase NCC abundance, and renal mRNA levels of its precursor angiotensinogen are increased 2-fold in B-129/Sv-4A11(+/+), and blockade of the ANGII receptor type 1 with losartan normalizes BP. A pro-hypertensive role for 20-HETE was implicated by normalization of BP and reversal of renal angiotensin mRNA increases by administration of the 20-HETE antagonists 2-((6Z,15Z)-20-hydroxyicosa-6,15-dienamido)acetate or (S)-2-((6Z,15Z)-20-hydroxyicosa-6,15-dienamido)succinate. SGK1 expression is also increased in B-129/Sv-4A11(+/+) mice and paralleled increases seen for NCC. Losartan, HET0016, and 20-HETE antagonists each normalized SGK1 mRNA expression. These results point to a potential 20-HETE dependence of intrarenal angiotensinogen production and ANGII receptor type 1 activation that are associated with increases in NCC and SGK1 and identify elevated P450 4A11 activity and 20-HETE as potential risk factors for salt-sensitive human hypertension by perturbation of the renal renin-angiotensin axis.
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037.
Üzen
Ü
Savas
the Departments of Medicine and.
Shouzou
S
Wei
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037.
Mei-Hui
MH
Hsu
the Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
John R
JR
Falck
Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and.
F Peter
FP
Guengerich
the Departments of Medicine and.
Jorge H
JH
Capdevila
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, johnson@scripps.edu.
Eric F
EF
Johnson
D000809:Angiotensins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D042926:Cytochrome P-450 CYP4A / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D064486:Solute Carrier Family 12, Member 3 / Q000096:biosynthesis / Q000235:genetics
C544066:Agtr1a protein, mouse; D000809:Angiotensins; D006893:Hydroxyeicosatetraenoic Acids; D044140:Receptor, Angiotensin, Type 1; C578875:Slc12a3 protein, mouse; D017673:Sodium Chloride, Dietary; D064486:Solute Carrier Family 12, Member 3; C465478:CYP4A11 protein, human; D042926:Cytochrome P-450 CYP4A; D019808:Losartan
cytochrome P450; eicosanoid specific enzyme; hypertension; renin angiotensin system; transgenic mice