uroguanylin and Nephrotic-Syndrome

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, isolated from human and opossum urine, is a candidate intestinal natriuretic hormone that controls the sodium and water balance between the intestine and the kidneys. Levels of immunoreactive (ir)-uroguanylin in the plasma and urine are increased in rats and humans with nephrotic syndrome, which is physiologically characterized by sodium retention with massive proteinuria. The present study evaluates the effect of natriuresis induced by uroguanylin on nephrotic rats.. Normal rats and rats rendered nephrotic by injections of puromycin aminonucleoside (PAN) were treated with uroguanylin (0.5 nmol/h, delivered by an osmotic pump) or with vehicle during the sodium retention phase. All rats consumed the same quantity of sodium.. Uroguanylin did not increase urinary excretion of sodium and water in normal rats, but significantly increased urinary sodium excretion during the sodium retention phase in nephrotic rats (untreated vs uroguanylin-treated nephrotic rats in mmol/mmol creatinine; 2.92 +/- 0.65 vs 8.93 +/- 2.53 on day 6, P < 0.05; 3.55 +/- 0.47 vs 10.37 +/- 1.73 on day 7, P < 0.01; 14.88 +/- 2.32 vs 24.47 +/- 2.86 on day 8, P < 0.05). Plasma levels of ir-uroguanylin in uroguanylin-treated nephrotic rats on day 6 were significantly increased compared with those in uroguanylin-treated control and untreated nephrotic rats.. Uroguanylin increased urinary sodium excretion in rats with PAN-induced nephrosis, and might be useful for treating sodium retention in patients with nephrotic syndrome.

Topics: Animals; Guanylate Cyclase; Male; Natriuresis; Natriuretic Peptides; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley

Uroguanylin induces natriuresis and diuresis in vivo as well as in vitro and is found mainly in the intestine and the kidney. However, the roles of uroguanylin in nephrotic syndrome, which is associated with sodium and water retention, have not been determined. Therefore, changes in the urine and plasma concentration of immunoreactive uroguanylin (ir-uroguanylin) and its mRNA expression in the kidney and intestine were examined using rats with puromycin aminonucleoside (PAN)-induced nephrosis. Male Sprague-Dawley rats were separated into control and nephrotic groups, and then the urinary excretion of sodium, protein, and ir-uroguanylin was examined over time. The plasma levels and renal and intestinal mRNA expression of uroguanylin at the periods of sodium retention and remarkable natriuresis also were evaluated. The sequential changes of urinary ir-uroguanylin excretion in the nephrotic group were similar to those of urinary sodium excretion. When the urinary excretion of ir-uroguanylin and sodium peaked, the plasma level of ir-uroguanylin also increased compared with that of the control group. Uroguanylin mRNA expression in the kidney increased during the period of sodium retention and then decreased during the period of remarkable natriuresis. Uroguanylin mRNA expression in the small intestines of control and nephrotic rats were identical. However, in a unilateral PAN-induced proteinuria, uroguanylin expression significantly increased in the PAN-perfused kidney compared with that in the opposite kidney. Considering the natriuretic effect of uroguanylin, these results suggested that uroguanylin plays an important role as a natriuretic factor in nephrotic syndrome via both the circulation and the kidney itself.

Topics: Animals; Atrial Natriuretic Factor; Base Sequence; Biomarkers; Disease Models, Animal; Male; Molecular Sequence Data; Natriuresis; Natriuretic Peptides; Nephrotic Syndrome; Peptides; Probability; Puromycin Aminonucleoside; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Animals; Biomarkers; Humans; Natriuretic Agents; Natriuretic Peptides; Nephrotic Syndrome; Peptides; Prognosis; Sensitivity and Specificity; Severity of Illness Index

Uroguanylin, a new natriuretic peptide originally isolated from urine, stimulates the membrane guanylate cyclase C receptor. No information, however, is available on the plasma and urine levels of uroguanylin in nephrotic syndrome (NS), the state associated with sodium and water retention. Using a sensitive radioimmunoassay, we measured the plasma and urine concentrations of immunoreactive (ir-)uroguanylin in NS patients and compared them with those of patients with non-nephrotic glomerulonephritis. Plasma ir-uroguanylin, blood pressure and the cardiothoracic ratio were higher, and urine excretion of ir-uroguanylin was lower in the NS patients. Plasma ir-uroguanylin in the NS patients significantly decreased during remission as compared with findings on admission. There was a significant inverse correlation between the concentration of plasma ir-uroguanylin and that of serum total protein or albumin. Moreover, fluid retention in the NS patients was correlated with the changes in plasma ir-uroguanylin between admission and remission, indicative that the plasma concentration increases with the severity of the nephrotic state. Taking into account its potent natriuretic effect, these findings suggest that uroguanylin may function in the pathophysiological mechanism in NS.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Female; Glomerulonephritis; Guanylate Cyclase; Humans; Kidney; Male; Natriuretic Peptides; Nephrotic Syndrome; Peptides; Serum Albumin