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

Üzen Savas, Shouzou Wei, Mei Hui Hsu, John R. Falck, F. Peter Guengerich, Jorge H. Capdevila, Eric F. Johnson

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)16904-16919
Number of pages16
JournalJournal of Biological Chemistry
Volume291
Issue number32
DOIs
StatePublished - Aug 5 2016

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Angiotensin Type 1 Receptor
Hydrochlorothiazide
Blood pressure
Transgenic Mice
Sodium
Blood Pressure
Hypertension
Angiotensinogen
Losartan
Angiotensins
Kidney
Renin
Angiotensin II
Messenger RNA
Sodium Chloride Symporters
Cytochrome P-450 CYP4A
129 Strain Mouse
Symporters
Sodium-Restricted Diet
Plasmas

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Molecular Biology
  • Cell Biology

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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. / Savas, Üzen; Wei, Shouzou; Hsu, Mei Hui; Falck, John R.; Guengerich, F. Peter; Capdevila, Jorge H.; Johnson, Eric F.

In: Journal of Biological Chemistry, Vol. 291, No. 32, 05.08.2016, p. 16904-16919.

Research output: Contribution to journalArticle

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abstract = "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.",
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AU - Savas, Üzen

AU - Wei, Shouzou

AU - Hsu, Mei Hui

AU - Falck, John R.

AU - Guengerich, F. Peter

AU - Capdevila, Jorge H.

AU - Johnson, Eric F.

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