Validation of uromodulin as a candidate gene for human essential hypertension

Graham, L. A. et al. (2014) Validation of uromodulin as a candidate gene for human essential hypertension. Hypertension, 63(3), pp. 551-558. (doi:10.1161/HYPERTENSIONAHA.113.01423)

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Publisher's URL: http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.01423

Abstract

A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na+ excretion and further Na+ loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fraser, Dr Niall and Graham, Mrs Lesley and Welsh, Dr Paul and Graham, Dr Delyth and McBride, Dr Martin and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Beattie, Mrs Wendy
Authors: Graham, L. A., Padmanabhan, S., Fraser, N. J., Kumar, S., Bates, J. M., Raffi, H. S., Welsh, P., Beattie, W., Hao, S., Leh, S., Hultstrom, M., Ferreri, N. R., Dominiczak, A. F., Graham, D., and McBride, M. W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
239331BHF ChairAnna DominiczakBritish Heart Foundation (BHF)CH/98001RI CARDIOVASCULAR & MEDICAL SCIENCES
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES
515251EuratransAnna DominiczakEuropean Commission (EC)241504RI CARDIOVASCULAR & MEDICAL SCIENCES
483571Collaborative strategy for a definitive genome scan in essential hypertension: high fidelity phenotyping and "hypercontrols"Anna DominiczakBritish Heart Foundation (BHF)SP/08/005/25115RI CARDIOVASCULAR & MEDICAL SCIENCES
570081Genetic, molecular and functional dissection of a novel pathway for hypertension: Uromodulin, renal function, sodium homeostasis and blood pressure.Sandosh PadmanabhanBritish Heart Foundation (BHF)PG/12/85/29925RI CARDIOVASCULAR & MEDICAL SCIENCES