Renal mechanisms of association between fibroblast growth factor 1 and blood pressure
Tomaszewski, M and Eales, J and Denniff, M and Myers, S and Chew, GS and Nelson, CP and Christofidou, P and Desai, A and Busst, C and Wojnar, L and Musialik, K and Jozwiak, J and Debiec, R and Dominiczak, AF and Navis, G and van Gilst, WH and van der Harst, P and Samani, NJ and Harrap, S and Bogdanski, P and Zukowska-Szczechowska, E and Charchar, FJ, Renal mechanisms of association between fibroblast growth factor 1 and blood pressure, Journal of the American Society of Nephrology, 26, (12) pp. 3151-3160. ISSN 1046-6673 (2015) [Refereed Article]
Copyright 2015 by the American Society of Nephrology
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.