Abstract
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 gene3,4,5,6,7,8,9, 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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Acknowledgements
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.
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M.T. and S.J. characterized the mouse model and carried out immunofluorescence and immunoblot analyses on mouse tissue; J.L. carried out expression studies for salt transporters; M.T. and C.S. performed RNA extraction and qRT-PCR analysis on mouse and human kidneys; M.T., S.J. and G.R. performed blood pressure measurements; S.J. and H.D. carried out plasma and urine analyses on mice; L.R., H.D. and M.T. did bioinformatics analysis; H.D. carried out in vitro analysis on the UMOD promoter; B.G. performed studies based on primary TAL cells. The SKIPOGH investigators provided the population-based cohort used for urinary uromodulin determination (H.D. and O.D.); P.M., C.L. and F.T. contributed to the hypertensive patient (MI_HPT) cohort patient recruitment and assessment; P.M. and C.L. designed and performed the study on human hypertensive patients; L.C. performed DNA extraction and genotyping on human samples; K.L. contributed in designing the in vitro experiments on Nkcc2 phosphorylation and activity that were performed by S.D.; G.D.A. and M.P.R. supervised the histology work on mouse and human kidneys; G.D.A., M.P.R. and M.I. carried out histological assessment; M.T. and M.I. performed histological and immunohistochemistry staining; L.R. and O.D. designed the study and supervised the experiments; L.R., O.D. and M.T. wrote the manuscript. All authors critically reviewed and approved the manuscript.
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Trudu, M., Janas, S., Lanzani, C. et al. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med 19, 1655–1660 (2013). https://doi.org/10.1038/nm.3384
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DOI: https://doi.org/10.1038/nm.3384
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