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 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1655-1660 |
| Number of pages | 6 |
| Journal | Nature Medicine |
| Volume | 19 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2013 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. / Trudu, Matteo; Janas, Sylvie; Lanzani, Chiara; Debaix, Huguette; Schaeffer, Céline; Ikehata, Masami; Citterio, Lorena; Demaretz, Sylvie; Trevisani, Francesco; Ristagno, Giuseppe; Glaudemans, Bob; Laghmani, Kamel; Dell'Antonio, Giacomo; Loffing, Johannes; Rastaldi, Maria P.; Manunta, Paolo; Devuyst, Olivier; Rampoldi, Luca; Bochud, Murielle; Burnier, Michel; Martin, Pierre Yves; Mohaupt, Markus; Paccaud, Fred; Pechère-Bertschi, Antoinette; Vogt, Bruno; Ackermann, Daniel; Ehret, Georg; Guessous, Idris; Ponte, Belen; Pruijm, Menno.
In: Nature Medicine, Vol. 19, No. 12, 12.2013, p. 1655-1660.Research output: Contribution to journal › Article
}
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
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.
UR - http://www.scopus.com/inward/record.url?scp=84889887136&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84889887136&partnerID=8YFLogxK
U2 - 10.1038/nm.3384
DO - 10.1038/nm.3384
M3 - Article
AN - SCOPUS:84889887136
VL - 19
SP - 1655
EP - 1660
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 12
ER -