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

Article Article scientifique Article Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression eng 2013 author Trudu Matteo author Janas Sylvie author Lanzani Chiara author Debaix Huguette author Schaeffer Céline 588634 author Ikehata Masami author Citterio Lorena author Demaretz Sylvie author Trevisani Francesco author Ristagno Giuseppe author Glaudemans Bob author Laghmani Kamel author Dell'Antonio Giacomo author Bochud Murielle 41043 author Burnier Michel author Martin Pierre-Yves 65591 author Mohaupt Markus author Paccaud Fred author Pechere Antoinette 120582 author Vogt Bruno author Ackermann Daniel author Ehret Georg Benedikt 98462 author Guessous Idris 760565 author Ponte Belen 89158 author Pruijm Menno 641036 author Loffing Johannes author Rastaldi Maria P author Manunta Paolo author Devuyst Olivier author Rampoldi Luca 1655-1660 10.1038/nm.3384 24185693 1078-8956 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. Adult Aged Animals Female Gene Expression Regulation Genetic Predisposition to Disease Genome-Wide Association Study Humans Hypertension/chemically induced/genetics Male Mice Mice, Transgenic Middle Aged Polymorphism, Single Nucleotide Promoter Regions, Genetic/genetics Renal Insufficiency, Chronic/genetics Sodium, Dietary/adverse effects/pharmacokinetics Up-Regulation Uromodulin/genetics Young Adult Dewey 613 Dewey 616 56 Département de médecine 221 64 Département de santé et médecine communautaires 22A false 16 Groupe Jean-Michel Gaspoz 23 99 Hypertension artérielle 128 Nature medicine 19 12 ffbfd2ff-3123-482b-ae48-0dd4023c74de Article (Published version) Restricted Trudu M_2013_Nat Med.pdf 1058443 application/pdf restrictedAccess Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département de santé et médecine communautaires

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Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression	Nature medicine	2013	652	0
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