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(Journal Article) |
Nature medicine 19 (12): 1655-60 (2013)
Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.
Matteo Trudu
,
Sylvie Janas
,
Chiara Lanzani
,
Huguette Debaix
,
Céline Schaeffer
,
Masami Ikehata
,
Lorena Citterio
,
Sylvie Demaretz
,
Francesco Trevisani
,
Giuseppe Ristagno
,
Bob Glaudemans
,
Kamel Laghmani
,
Giacomo Dell'Antonio
,
Murielle Bochud
,
Michel Burnier
,
Olivier Devuyst
,
Pierre-Yves Martin
,
Markus Mohaupt
,
Fred Paccaud
,
Antoinette Pechère-Bertschi
,
Bruno Vogt
,
Daniel Ackermann
,
Georg Ehret
,
Idris Guessous
,
Belen Ponte
,
Menno Pruijm
,
Johannes Loffing
,
Maria P Rastaldi
,
Paolo Manunta
,
Luca Rampoldi
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.