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Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure

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posted on 2015-05-07, 10:41 authored by Maciej Tomaszewski, James Eales, Matthew Denniff, S. Myers, G. S. Chew, Christopher P. Nelson, Paraskevi Christofidou, Aishwarya Desai, C. Büsst, L. Wojnar, K. Musialik, J. Jozwiak, Radoslaw Debiec, A. F. Dominiczak, G. Navis, W. H. van Gilst, Pim van der Harst, Nilesh J. Samani, S. Harrap, P. Bogdanski, E. Zukowska-Szczechowska, Fadi J. Charchar
Fibroblast growth factor 1 gene - FGF1 - is expressed primarily in the kidney and is postulated to contribute to hypertension. However, the biological mechanisms underlying the association between FGF1 and blood pressure regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner not only with systolic blood pressure (P=9.65x10-5) and diastolic blood pressure (7.61x10-3) in a meta-analysis of 14364 individuals but also with renal expression of FGF1 mRNA in 126 human kidneys (9.0x10-3). Next-generation RNA-sequencing revealed that renal upregulation of FGF1 expression globally and of each of its 3 mRNA isoforms individually is associated with higher blood pressure. FGF1-stratified co-expression analysis in 2 separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic blood pressure, respectively. Of those, 7 mRNAs in 5 genes (MME, PTPRO, REN, SLC12A3 and WNK1) had strong prior annotation to blood pressure or hypertension. MME (that encodes an enzyme responsible for degradation of circulating natriuretic peptides) showed the strongest differential co-expression with FGF1 between hypertensive and normotensive kidneys. Higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes in natriuretic peptides catabolism pathway, reninangiotensin cascade and sodium handling network may explain the association between FGF1 and blood pressure.

Funding

This work was supported by grants from the National Health & Medical Research Council of Australia, the Federation University Australia 'Self-sustaining Regions Research and Innovation Initiative', an Australian Government Collaborative Research Network grant (to F.J.C.) and British Heart Foundation (PG/12/9/29376 to MT and JE). AFD was a holder of British Heart Foundation Chair in Cardiovascular Medicine. NJS holds a British Heart Foundation Chair in Cardiology and is a NIHR Senior Investigator. This work is a part of the portfolio of research supported by NIHR Leicester Biomedical Research Unit in Cardiovascular Disease.

History

Citation

Journal of the American Society of Nephrology April 27, 2015 ASN.2014121211

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

  • AM (Accepted Manuscript)

Published in

Journal of the American Society of Nephrology April 27

Publisher

American Society of Nephrology

issn

1046-6673

eissn

1533-3450

Available date

2015-11-11

Publisher version

http://jasn.asnjournals.org/content/early/2015/04/27/ASN.2014121211

Notes

The extended version of the statistical and bioinformatics analysis is available in Supplementary material.

Language

en

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