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

Jacek Jozwiak, Fadi J Charchar, Ewa Zukowska-Szczechowska, Pawel Bogdanski, Stephen Harrap, Nilesh J Samani, Pim van der Harst, Wiek H van Gilst, Gerjan Navis, Anna F Dominiczak, Radoslaw Debiec, Maciej Tomaszewski, Katarzyna Musialik, Lukasz Wojnar, Cara Büsst, Aishwarya Desai, Paraskevi Christofidou, Christopher P Nelson, Guat Siew Chew, Stephen Myers, Matthew Denniff, James Eales

Journal: Journal of the American Society of Nephrology : JASN 2016;26(12):3151-60

PMID: 25918036

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Abstract

The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P = 9.65 × 10(-5)) and diastolic BP (P = 7.61 × 10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0 × 10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.

Address: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Biomedical Research Centre in Cardiovascular Disease, Leicester, United Kingdom; [email protected].; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom;; Faculty of Science and Technology, Federation University Australia, Ballarat, Australia;; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Biomedical Research Centre in Cardiovascular Disease, Leicester, United Kingdom;; Department of Physiology, University of Melbourne, Melbourne, Australia;; Departments of Urology and.; Education and Obesity Treatment and Metabolic Disorders, Poznan University of Medical Sciences, Poznan, Poland;; Department of Public Health, Czestochowa University of Technology, Czestochowa, Poland;; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;; Departments of Internal Medicine and.; Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands; and.; Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland.; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; Faculty of Science and Technology, Federation University Australia, Ballarat, Australia;

DOI: 10.1681/ASN.2014121211