title: Validation of uromodulin as a candidate gene for human essential hypertension.
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.
authors: Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. Martin.McBride@glasgow.ac.uk.
authors: Lesley A
authors: LA
authors: Graham
authors: Sandosh
authors: S
authors: Padmanabhan
authors: Niall J
authors: NJ
authors: Fraser
authors: Satish
authors: S
authors: Kumar
authors: James M
authors: JM
authors: Bates
authors: Hajamohideen S
authors: HS
authors: Raffi
authors: Paul
authors: P
authors: Welsh
authors: Wendy
authors: W
authors: Beattie
authors: Shoujin
authors: S
authors: Hao
authors: Sabine
authors: S
authors: Leh
authors: Michael
authors: M
authors: Hultstrom
authors: Nicholas R
authors: NR
authors: Ferreri
authors: Anna F
authors: AF
authors: Dominiczak
authors: Delyth
authors: D
authors: Graham
authors: Martin W
authors: MW
authors: McBride
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000075222:Essential Hypertension; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D058949:Uromodulin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D058949:Uromodulin; D012313:RNA
keywords: Umod protein, mouse; hypertension; mice; mice, knockout; uromodulin