uroguanylin and Heart-Failure

The uroguanylin system is a newly discovered endocrine/paracrine system that may have a role in the regulation of salt balance, appetite and gut health. The precursor pro-uroguanylin is predominantly synthesized in the gut, although there may be other sites of synthesis, including the kidney tubules. Products from pro-uroguanylin may mediate natriuresis following oral consumption of a salt load through both GC-C (guanylate cyclase C)-dependent and -independent mechanisms, and recent evidence suggests a role in appetite regulation. Local paracrine effects in the gut through GC-C stimulation may have tumour-suppressing actions through the regulation of cell proliferation and metabolism. Although most information on this system has been derived from knockout models, recent human studies have indicated possible roles in heart failure and renal failure. An improved understanding of the nature of its natriuretic, appetite and tumour-suppressing actions may facilitate the discovery of new therapies for heart failure, obesity and cancer prophylaxis.

Topics: Amino Acid Sequence; Appetite Regulation; Colonic Neoplasms; Endocrine System; Heart Failure; Humans; Hypertension; Intestinal Mucosa; Irritable Bowel Syndrome; Kidney; Models, Biological; Molecular Sequence Data; Natriuretic Peptides; Paracrine Communication; Receptors, Guanylate Cyclase-Coupled; Signal Transduction; Species Specificity

The guanylate cyclase activator 2B, also known as uroguanylin, is part of the guanylin peptide family, which includes peptides such as guanylin and lymphoguanylin. The guanylin peptides could be related to sodium absorption inhibition and water secretion induction and their dysfunction may be related to various pathologies such as chronic renal failure, congestive heart failure and nephrotic syndrome. Besides, uroguanylin point mutations have been associated with essential hypertension. However, currently there are no studies on the impact of missense SNPs on uroguanylin structure. This study applied in silico SNP impact prediction tools to evaluate the impact of uroguanylin missense SNPs and to filter those considered as convergent deleterious, which were then further analyzed through long-term molecular dynamics simulations of 1μs of duration. The simulations suggested that all missense SNPs considered as convergent deleterious caused some kind of structural change to the uroguanylin peptide. Additionally, four of these SNPs were also shown to cause modifications in peptide flexibility, possibly resulting in functional changes.

Topics: Heart Failure; Humans; Kidney Failure, Chronic; Molecular Dynamics Simulation; Mutation, Missense; Natriuretic Peptides; Nephrotic Syndrome; Polymorphism, Single Nucleotide; Structure-Activity Relationship

Uroguanylin is a small-molecular-weight peptide that activates membrane-bound receptor-guanylate cyclases in the intestine, kidney, and other epithelia. Uroguanylin has been shown to participate in the regulation of salt and water homeostasis in mammals via cGMP-mediated processes, bearing a distinct similarity to the action of the atriopeptins, which play a defined role in natriuresis and act as prognostic indicators of severe congestive heart failure (CHF). The objectives of this study were to measure the urinary levels of uroguanylin and the circulating plasma levels of atrial natriuretic peptide (ANP) in healthy individuals (n = 53) and patients with CHF (n = 16). Urinary excretion of uroguanylin was assessed by a cGMP accumulation bioassay employing human T84 intestinal cells. In individuals without CHF, the concentration of uroguanylin bioactivity was 1.31 +/- 0.27 nmol cGMP/ml urine and 1.73 +/- 0.25 micromol cGMP/24-h urine collection. The urinary bioactivity of uroguanylin in males (1.74 +/- 0.55 nmol cGMP/ml urine; n = 27) tended to be higher than the excretion levels in females (0.94 +/- 0.16 nmol cGMP/ml urine; n = 26) over a 24-h period but did not achieve statistical significance. Both male and female groups showed 24-h temporal diurnal variations with the highest uroguanylin levels observed between the hours of 8:00 AM and 2:00 PM. The circulating level of ANP was 12.1 +/- 1.6 pg/ml plasma and did not significantly vary with respect to male/female population or diurnal variation. In patients with CHF, the concentration of plasma ANP and urinary uroguanylin bioactivity increased substantially (7.5-fold and 70-fold, respectively, both P

Topics: Adult; Aged; Aged, 80 and over; Aging; Atrial Natriuretic Factor; Cell Line; Circadian Rhythm; Cyclic GMP; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptides; Peptides; Reference Values; Sex Characteristics