Urotensin-II System in Genetic Control of Blood Pressure and Renal Function

Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates

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

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