Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure.
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.
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Biomedical Research Centre in Cardiovascular Disease, Leicester, United Kingdom; mt142@le.ac.uk.
Maciej
M
Tomaszewski
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom;
James
J
Eales
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom;
Matthew
M
Denniff
Faculty of Science and Technology, Federation University Australia, Ballarat, Australia;
Stephen
S
Myers
Faculty of Science and Technology, Federation University Australia, Ballarat, Australia;
Guat Siew
GS
Chew
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Biomedical Research Centre in Cardiovascular Disease, Leicester, United Kingdom;
Christopher P
CP
Nelson
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom;
Paraskevi
P
Christofidou
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom;
Aishwarya
A
Desai
Department of Physiology, University of Melbourne, Melbourne, Australia;
Cara
C
Büsst
Departments of Urology and.
Lukasz
L
Wojnar
Education and Obesity Treatment and Metabolic Disorders, Poznan University of Medical Sciences, Poznan, Poland;
Katarzyna
K
Musialik
Department of Public Health, Czestochowa University of Technology, Czestochowa, Poland;
Jacek
J
Jozwiak
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom;
Radoslaw
R
Debiec
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom;
Anna F
AF
Dominiczak
Departments of Internal Medicine and.
Gerjan
G
Navis
Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
Wiek H
WH
van Gilst
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.
Pim
P
van der Harst
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Biomedical Research Centre in Cardiovascular Disease, Leicester, United Kingdom;
Nilesh J
NJ
Samani
Department of Physiology, University of Melbourne, Melbourne, Australia;
Stephen
S
Harrap
Education and Obesity Treatment and Metabolic Disorders, Poznan University of Medical Sciences, Poznan, Poland;
Pawel
P
Bogdanski
Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland.
Ewa
E
Zukowska-Szczechowska
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; Faculty of Science and Technology, Federation University Australia, Ballarat, Australia;
Fadi J
FJ
Charchar
D000293:Adolescent; D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000235:genetics*; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007668:Kidney / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D015260:Neprilysin / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics; D012083:Renin / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics; D000076204:WNK Lysine-Deficient Protein Kinase 1; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3; D016220:Fibroblast Growth Factor 1; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C516888:PTPRO protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D012083:Renin; D015260:Neprilysin
blood pressure; gene expression; gene transcription; glomerulus; hypertension; kidney