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Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression

Trudu, Matteo
Janas, Sylvie
Lanzani, Chiara
Debaix, Huguette
Ikehata, Masami
Citterio, Lorena
Demaretz, Sylvie
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Published in Nature medicine. 2013, vol. 19, no. 12, p. 1655-60
Abstract Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.
Keywords AdultAgedAnimalsFemaleGene Expression RegulationGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansHypertension/chemically induced/geneticsMaleMiceMice, TransgenicMiddle AgedPolymorphism, Single NucleotidePromoter Regions, Genetic/geneticsRenal Insufficiency, Chronic/geneticsSodium, Dietary/adverse effects/pharmacokineticsUp-RegulationUromodulin/geneticsYoung Adult
PMID: 24185693
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Research groups Groupe Jean-Michel Gaspoz (23)
Hypertension artérielle (128)
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TRUDU, Matteo et al. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. In: Nature Medicine, 2013, vol. 19, n° 12, p. 1655-60. doi: 10.1038/nm.3384 https://archive-ouverte.unige.ch/unige:40971

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Deposited on : 2014-10-17

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