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.

Author information

Author notes

    • Olivier Devuyst
    •  & Luca Rampoldi

    These authors contributed equally to this work.

Affiliations

  1. Dulbecco Telethon Institute, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.

    • Matteo Trudu
    • , Céline Schaeffer
    •  & Luca Rampoldi
  2. Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

    • Sylvie Janas
    • , Huguette Debaix
    • , Bob Glaudemans
    •  & Olivier Devuyst
  3. Division of Nephrology, Université catholique de Louvain, Medical School, Brussels, Belgium.

    • Sylvie Janas
    • , Huguette Debaix
    •  & Olivier Devuyst
  4. Division of Nephrology and Dialysis, San Raffaele Scientific Institute, Milan, Italy.

    • Chiara Lanzani
    •  & Lorena Citterio
  5. Renal Research Laboratory, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

    • Masami Ikehata
    •  & Maria P Rastaldi
  6. Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy.

    • Masami Ikehata
    •  & Maria P Rastaldi
  7. INSERM UMRS 872, Paris, France.

    • Sylvie Demaretz
    •  & Kamel Laghmani
  8. School of Nephrology, University Vita-Salute San Raffaele, Milan, Italy.

    • Francesco Trevisani
    •  & Paolo Manunta
  9. Department of Cardiovascular Research, Istituto di Ricerce Farmacologiche Mario Negri, Milan, Italy.

    • Giuseppe Ristagno
  10. Department of Pathology, San Raffaele Scientific Institute, Milan, Italy.

    • Giacomo Dell'Antonio
  11. Institute of Anatomy, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

    • Idris Guessous
    •  & Johannes Loffing
  12. Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.

    • Murielle Bochud
    •  & Fred Paccaud
  13. Department of Nephrology, Lausanne University Hospital, Lausanne, Switzerland.

    • Michel Burnier
    •  & Menno Pruijm
  14. Department of Nephrology, Geneva University Hospitals, Geneva, Switzerland.

    • Pierre-Yves Martin
    •  & Belen Ponte
  15. Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.

    • Markus Mohaupt
    • , Bruno Vogt
    •  & Daniel Ackermann
  16. Hypertension Unit, Geneva University Hospitals, Geneva, Switzerland.

    • Antoinette Pechère-Bertschi
  17. Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.

    • Georg Ehret
  18. Unit of Population Epidemiology, Division of Primary Care Medicine, Department of Community Medicine and Primary Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland.

    • Idris Guessous

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  1. the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) team

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Olivier Devuyst or Luca Rampoldi.

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https://doi.org/10.1038/nm.3384

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