Abstract
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.
Highlights
Urotensin-II (U-II) is an eleven amino-acid peptide first extracted from neurophysis of Goby fish (Gillichthys mirabilis) [1]
Both clinic systolic BP (SBP) and clinic diastolic BP (DBP) showed substantial heritable component estimated in the range of 30.5% (SBP in the GRAPHIC Study) to 47.1% (SBP in Silesian Cardiovascular Study (SCS) families) (Table 2)
Our data show that common genetic variation in U-II pathway is unlikely to play a major role in genetic regulation of human blood pressure (BP) or estimated GFR (eGFR)
Summary
Urotensin-II (U-II) is an eleven amino-acid peptide first extracted from neurophysis (neuro-secretory organ) of Goby fish (Gillichthys mirabilis) [1]. Native to the Gulf of California, Goby fish is known for its exceptional ability to withstand profound changes in temperature and osmolality of the aquatic environment [2]. One of the mechanisms involved in Goby’s adaptation to rapidly changing osmolality is U-II [3]. Upregulation of U-II pathway in Goby fish translates into inhibition of NaCl transport in a concentration dependent manner [4]. These data indicate that U-II system contributes to fish osmoregulation and ion-exchange; both of which are regulated by the mammalian kidney
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