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

Détails

ID Serval
serval:BIB_C399FC2ECDDE
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.
Périodique
Nature Medicine
Auteur(s)
Trudu M., Janas S., Lanzani C., Debaix H., Schaeffer C., Ikehata M., Citterio L., Demaretz S., Trevisani F., Ristagno G., Glaudemans B., Laghmani K., Dell'antonio G., Bochud M., Bochud M., Burnier M., Devuyst O., Martin P.Y., Mohaupt M., Paccaud F., Pechère-Bertschi A., Vogt B., Ackermann D., Ehret G., Guessous I., Ponte B., Pruijm M., Loffing J., Rastaldi M.P., Manunta P., Devuyst O., Rampoldi L.
Collaborateur(s)
Swiss Kidney Project on Genes in Hypertension (SKIPOGH) team
Contributeur(s)
Bochud M., Burnier M., Devuyst O., Martin PY., Mohaupt M., Paccaud F., Pechère-Bertschi A., Vogt B., Ackermann D., Ehret G., Guessous I., Ponte B., Pruijm M.
ISSN
1546-170X (Electronic)
ISSN-L
1078-8956
Statut éditorial
Publié
Date de publication
2013
Volume
19
Numéro
12
Pages
1655-1660
Langue
anglais
Notes
Publication types: Journal ArticlePublication Status: ppublish. Murielle Bochud, Michel Burnier, Fred Paccaud, Idris Guessous et Menno Pruijm font partie de SKIPOGH team. pdf type: letter as journal article (nature medicine)
Résumé
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.
Pubmed
Web of science
Création de la notice
10/12/2013 11:41
Dernière modification de la notice
03/03/2018 21:12
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