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Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression
Elevated blood pressure (BP) and chronic kidney disease (CKD) are complex traits representing major global health problems(1,2). Multiple genome-wide association studies (GWAS) identified common variants giving independent susceptibility for CKD and hypertension in the promoter of the UMOD gene(3-9)...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856354/ https://www.ncbi.nlm.nih.gov/pubmed/24185693 http://dx.doi.org/10.1038/nm.3384 |
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author | 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 |
author_facet | 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 |
author_sort | Trudu, Matteo |
collection | PubMed |
description | Elevated blood pressure (BP) and chronic kidney disease (CKD) are complex traits representing major global health problems(1,2). Multiple genome-wide association studies (GWAS) identified common variants giving independent susceptibility for CKD and hypertension in the promoter of the UMOD gene(3-9), encoding uromodulin, the major protein secreted in the normal urine. Despite compelling genetic evidence, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants directly increase UMOD expression in vitro and in vivo. We modeled this effect in transgenic mice and showed that uromodulin overexpression leads to salt-sensitive hypertension and to age-dependent renal lesions that are similarly observed in elderly subjects homozygous for UMOD risk variants. We demonstrate that the link between uromodulin and hypertension is caused by activation of the renal sodium co-transporter NKCC2. This very mechanism is relevant in humans, as pharmacological inhibition of NKCC2 is more effective in lowering BP in hypertensive patients homozygous for UMOD risk variants. Our findings establish a link between the genetic susceptibility to hypertension and CKD, the control of uromodulin expression and its role in a salt-reabsorbing tubular segment of the kidney. These data point to uromodulin as a novel therapeutic target to lower BP and preserve renal function. |
format | Online Article Text |
id | pubmed-3856354 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-38563542014-06-01 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 Nat Med Article Elevated blood pressure (BP) and chronic kidney disease (CKD) are complex traits representing major global health problems(1,2). Multiple genome-wide association studies (GWAS) identified common variants giving independent susceptibility for CKD and hypertension in the promoter of the UMOD gene(3-9), encoding uromodulin, the major protein secreted in the normal urine. Despite compelling genetic evidence, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants directly increase UMOD expression in vitro and in vivo. We modeled this effect in transgenic mice and showed that uromodulin overexpression leads to salt-sensitive hypertension and to age-dependent renal lesions that are similarly observed in elderly subjects homozygous for UMOD risk variants. We demonstrate that the link between uromodulin and hypertension is caused by activation of the renal sodium co-transporter NKCC2. This very mechanism is relevant in humans, as pharmacological inhibition of NKCC2 is more effective in lowering BP in hypertensive patients homozygous for UMOD risk variants. Our findings establish a link between the genetic susceptibility to hypertension and CKD, the control of uromodulin expression and its role in a salt-reabsorbing tubular segment of the kidney. These data point to uromodulin as a novel therapeutic target to lower BP and preserve renal function. 2013-11-03 2013-12 /pmc/articles/PMC3856354/ /pubmed/24185693 http://dx.doi.org/10.1038/nm.3384 Text en Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article 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 Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression |
title | Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression |
title_full | Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression |
title_fullStr | Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression |
title_full_unstemmed | Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression |
title_short | Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression |
title_sort | common noncoding umod gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856354/ https://www.ncbi.nlm.nih.gov/pubmed/24185693 http://dx.doi.org/10.1038/nm.3384 |
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