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

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Trudu, Matteo Janas, Sylvie Lanzani, Chiara Debaix, Huguette Schaeffer, Céline Devuyst, Olivier [UCL] Rampoldi, Luca

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.

Document type Article de périodique (Journal article)
Access type Accès restreint
Publication date 2013
Language Anglais
Journal information "Nature Medicine" - Vol. 19, no.12, p. 1655-60 (2013)
Peer reviewed yes
Publisher Nature Publishing Group ((United States) New York)
issn 1078-8956
e-issn 1546-170X
Publication status Publié
Affiliations UCL - SSS/IREC/NEFR - Pôle de Néphrologie
UCL - (SLuc) Service de néphrologie
MESH Subject Adult ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Renal Insufficiency, Chronic ; Sodium, Dietary ; Up-Regulation ; Uromodulin ; Aged ; Young Adult ; Animals ; Female ; Gene Expression Regulation ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Hypertension
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Bibliographic reference Trudu, Matteo ; Janas, Sylvie ; Lanzani, Chiara ; Debaix, Huguette ; Schaeffer, Céline ; et. al. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.. In: Nature Medicine, Vol. 19, no.12, p. 1655-60 (2013)
Permanent URL http://hdl.handle.net/2078.1/144724