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

Trudu, M.; Janas, S.; Lanzani, C.; Debaix, H.; Schaeffer, C.; Ikehata, M.; Citterio, L.; Demaretz, S.; Trevisani, F.; Ristagno, G.; Glaudemans, B.; Laghmani, K.; Dell'antonio, G.; Bochud, M.; Burnier, M.; Martin, P. Y.; Mohaupt, Markus; Paccaud, F.; Péchère-Bertschi, A.; Vogt, Bruno; ... (2013). Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nature medicine, 19(12), pp. 1655-1660. Nature Publishing Group 10.1038/nm.3384

[img]
Preview
Text
2013-PaperDevuyst.pdf - Published Version
Available under License Publisher holds Copyright.

Download (959kB) | Preview
[img] Text
2013-PaperDevuyst.pdf
Restricted to registered users only
Available under License BORIS Standard License.

Download (959kB) | Request a copy

Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems1,2. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene3–9, 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie

UniBE Contributor:

Mohaupt, Markus; Vogt, Bruno and Ackermann, Daniel

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1078-8956

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Daniel Ackermann

Date Deposited:

13 Jun 2014 17:25

Last Modified:

26 Jun 2016 01:51

Publisher DOI:

10.1038/nm.3384

PubMed ID:

24185693

BORIS DOI:

10.7892/boris.48779

URI:

https://boris.unibe.ch/id/eprint/48779

Actions (login required)

Edit item Edit item
Provide Feedback