title: Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.
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.
authors.affiliation: Dulbecco Telethon Institute, c/o Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Trudu
authors.affiliation: Institute of Physiology, Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.|Division of Nephrology, UCL Medical School, Brussels, Belgium.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Janas
authors.affiliation: Division of Nephrology and Dialysis, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Lanzani
authors.affiliation: Institute of Physiology, Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.|Division of Nephrology, UCL Medical School, Brussels, Belgium.
authors.forename: Huguette
authors.initials: H
authors.lastname: Debaix
authors.affiliation: Dulbecco Telethon Institute, c/o Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Céline
authors.initials: C
authors.lastname: Schaeffer
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico & Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy.
authors.forename: Masami
authors.initials: M
authors.lastname: Ikehata
authors.affiliation: Division of Nephrology and Dialysis, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.affiliation: INSERM, UMRS 872, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Demaretz
authors.affiliation: University Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trevisani
authors.affiliation: Department of Cardiovascular Research, Istituto di Ricerca Farmacologica Mario Negri, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ristagno
authors.affiliation: Institute of Physiology, Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Bob
authors.initials: B
authors.lastname: Glaudemans
authors.affiliation: INSERM, UMRS 872, Paris, France.
authors.forename: Kamel
authors.initials: K
authors.lastname: Laghmani
authors.affiliation: Department of Pathology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Dell'Antonio
authors.affiliation: Institute of Anatomy, Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico & Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rastaldi
authors.affiliation: University Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
authors.affiliation: Institute of Physiology, Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: Dulbecco Telethon Institute, c/o Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rampoldi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051436:Renal Insufficiency, Chronic / Q000235:genetics*; D012982:Sodium, Dietary / Q000009:adverse effects / Q000493:pharmacokinetics; D015854:Up-Regulation; D058949:Uromodulin / Q000235:genetics*; D055815:Young Adult
chemical_list: D012982:Sodium, Dietary; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin