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CYP4A11 T8590C polymorphism, salt-sensitive hypertension, and renal blood flow.

ABSTRACT: A loss-of-function cytosine (C) for thymidine (T) transition at nucleotide 8590 of CYP4A11 has been associated with increased blood pressure in humans. We tested the hypothesis that CYP4A11 T8590C genotype is associated with salt sensitivity in the International Hypertensive Pathotype cohort.CYP4A11 T8590C genotype was associated with hypertension in whites. Among normotensive individuals, CYP4A11 T8590C genotype was associated with mean arterial pressure (MAP) during both high and low salt diets, such that there was no relationship between genotype and salt sensitivity of blood pressure. Among hypertensive individuals, CYP4A11 T8590C genotype did not associate with MAP during high salt intake, whereas MAP decreased with increasing number of C alleles during salt restriction. Consequently, among hypertensive individuals, change in MAP with salt restriction was greatest in individuals homozygous for the C allele (-10.9?±?9.9, -11.1?±?12.3, and -18.8?±?12.0?mmHg in TT, CT, and CC groups, respectively, P?=?0.02). In both normotensive and hypertensive individuals, individuals homozygous for the C allele exhibited an attenuated increase in renal blood flow during high salt. CYP4A11 genotype did not affect pressor responses to Angiotensin II in normotensive or hypertensive individuals.The loss-of-function CYP4A11 8590C allele is associated with a diagnosis of hypertension and, in normotensive individuals, with higher blood pressure regardless of salt intake. Among hypertensive individuals, the C allele is associated with salt-sensitive blood pressure. Impaired renal vasodilation during high salt intake may contribute to salt sensitivity. Studies are needed to determine whether CYP4A11 T8590C genotype predicts responses to medications that affect sodium homeostasis in hypertensive individuals.

SUBMITTER: Williams JS

PROVIDER: S-EPMC3309034 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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CYP4A11 T8590C polymorphism, salt-sensitive hypertension, and renal blood flow.

Williams Jonathan S JS Hopkins Paul N PN Jeunemaitre Xavier X Brown Nancy J NJ

Journal of hypertension 20111001 10

<h4>Objective and methods</h4>A loss-of-function cytosine (C) for thymidine (T) transition at nucleotide 8590 of CYP4A11 has been associated with increased blood pressure in humans. We tested the hypothesis that CYP4A11 T8590C genotype is associated with salt sensitivity in the International Hypertensive Pathotype cohort.<h4>Results</h4>CYP4A11 T8590C genotype was associated with hypertension in whites. Among normotensive individuals, CYP4A11 T8590C genotype was associated with mean arterial pre ...[more]

PMID: 21873888

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Project description:AimsRenal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension.Methods and resultsC57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25-40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na+], and albuminuria (each by 20-25%). None of the above parameters were altered by MCC950 in normotensive mice.ConclusionMCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy.

Dataset Information

CYP4A11 T8590C polymorphism, salt-sensitive hypertension, and renal blood flow.

Publications

CYP4A11 T8590C polymorphism, salt-sensitive hypertension, and renal blood flow.

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