TY - JOUR
T1 - Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression
AU - Trudu, Matteo
AU - Janas, Sylvie
AU - Lanzani, Chiara
AU - Debaix, Huguette
AU - Schaeffer, Céline
AU - Ikehata, Masami
AU - Citterio, Lorena
AU - Demaretz, Sylvie
AU - Trevisani, Francesco
AU - Ristagno, Giuseppe
AU - Glaudemans, Bob
AU - Laghmani, Kamel
AU - Dell'Antonio, Giacomo
AU - Loffing, Johannes
AU - Rastaldi, Maria P.
AU - Manunta, Paolo
AU - Devuyst, Olivier
AU - Rampoldi, Luca
AU - Bochud, Murielle
AU - Burnier, Michel
AU - Martin, Pierre Yves
AU - Mohaupt, Markus
AU - Paccaud, Fred
AU - Pechère-Bertschi, Antoinette
AU - Vogt, Bruno
AU - Ackermann, Daniel
AU - Ehret, Georg
AU - Guessous, Idris
AU - Ponte, Belen
AU - Pruijm, Menno
N1 - Funding Information:
We thank M. Azizi, A. Blanchard, G. Capasso, M. Carrel, Y. Cnops, A. Creatore, S. Delli Carpini, P. Houillier, X. Jeunemaitre, R. Latini, N. Morel, S. Terryn and S. Youhanna for help, technical assistance and fruitful discussions. We are grateful to S. Bourgeois (University of Zurich) for providing MKTAL cells, to D. Alessi (University of Dundee) for antibodies to SPAK and phospho-SPAK/OSR1, to B. Forbush (Yale University) for antibody to phospho-NKCC2 and to D. Schock-Kusch and N. Gretz (University of Heidelberg) for FITC-sinistrin clearance reagents and technical assistance. This work was supported by Telethon-Italy (TCR08006), the Italian Ministry of Health (grant RF-2010-2319394), Associazione per il Bambino Nefropatico, the Belgian Fonds National de la Recherche Scientifique and Fonds pour la Recherche Scientifique Médicale, a Concerted Research Action (10/15-029), an Interuniversity Attraction Pole program initiated by the Belgian Science Policy Office, the Gebert Rüf Stiftung (Project GRS-038/12), the National Centre of Competence in Research Kidney. CH (Swiss National Science Foundation), the Swiss National Science Foundation project grant 310030_146490 and the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 246539 (Marie Curie) and grant 305608 (EURenOmics). The SKIPOGH project is funded by the Swiss National Science Foundation (33CM30-124087/1 and 33CM30_140331). L.R. is an Associate Telethon Scientist.
PY - 2013/12
Y1 - 2013/12
N2 - 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 3-9, 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.
AB - 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 3-9, 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.
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U2 - 10.1038/nm.3384
DO - 10.1038/nm.3384
M3 - Article
C2 - 24185693
AN - SCOPUS:84889887136
SN - 1078-8956
VL - 19
SP - 1655
EP - 1660
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -