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.

Background: The novel peptide, uroguanylin, is mainly produced in the intestine and causes natriuresis via cyclic GMP (cGMP) activation. Uroguanylin plays an important role in sodium transport in the gastrointestinal tract and functions as an intestinal natriuretic hormone during oral salt load. However, the role and behavior of uroguanylin in the kidneys during high salt load remains unknown. Methods: We measured the uroguanylin concentrations in the urine and plasma of rats fed with low or high salt diets for 1 week, using a sensitive radioimmunoassay (RIA). Urinary cGMP and electrolyte excretion was also measured. Intestinal and renal expression of uroguanylin mRNA was evaluated by Northern blotting and by reverse transcription-polymerase chain reaction (RT-PCR). Results: The urinary excretion of immunoreactive (ir-) uroguanylin in rats on the high salt diet was significantly higher than that in the low salt group (425 ± 107 vs. 128 ± 8.5 pmol/day, p < 0.01) and significantly correlated with urinary Na⁺ and cGMP excretion. Plasma ir-uroguanylin levels between the two groups did not significantly differ. Uroguanylin mRNA expression was increased both in the intestine and kidneys of rats on the high salt diet. Conclusion: These findings suggest that uroguanylin regulates sodium metabolism in the intestine and kidneys during oral salt load in an autocrine and paracrine manner.

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. U roguanylin is a small peptide that activates transmembrane guanylate cyclase (GC) C, influences cellular function via intracellular cyclic guanosine monophosphate (cGMP) (1), and induces the urinary excretion of sodium and water in isolated perfused rat kidneys (2) and in mice in vivo (3). Uroguanylin and guanylin are major hormones in one family of cGMP agonists, whereas atriopeptins (atrial natriuretic peptide [ANP], brain natriuretic peptide, and C-type natriuretic peptide) are a separate and distinct family of peptides that act on different GC (GC-A, -B) to signal via cGMP. We reported that uroguanylin excretion into the urine is increased in humans and rats on a high-salt diet compared with those on a low-salt diet (4,5), indicating that uroguanylin functions as an intestinal natriuretic peptide. Moreover, uroguanylin levels are increased in the circulation of patients with renal disease and congestive heart failure (6,7). Forte et al. (8) suggested that uroguanylin participates in the physiologic maintenance of the sodium balance. However, how uroguanylin functions in the pathophysiologic mechanism of nephrotic syndrome, a condition associated with sodium and water retention, remains obscure. The present study examined serial changes in the urine and plasma concentration of immunoreactive urogua...

Background: Uroguanylin, originally isolated from urine, is a new natriuretic peptide. Its plasma level is increased in association with renal impairment and fluid retention in patients with renal diseases. Methods: Uroguanylin concentrations were measured in patients on hemodialysis (HD, n = 76) and those on continuous ambulatory peritoneal dialysis (CAPD, n = 10) using a sensitive ra- dioimmunoassay for human uroguanylin. Results: Plasma concentrations of immunoreactive (ir)-uroguanylin in the patients on HD and CAPD (212.0 ± 17.4 and 245.3 ± 39.5 fmol/ml) were significantly higher than the value for the normal controls (5.0 ± 0.3 fmol/ml). Plasma ir-uroguanylin levels before the start of regular HD were correlated with predialysis excess weight based on their dry weights (r = 0.33, p < 0.01) and with dialysis duration (r = 0.26, p < 0.05). The plasma levels in patients with HD, for whom high-flux membranes were used, were decreased at the end of regular HD as compared with the prior levels (p < 0.05), but not in those who underwent HD with conventional membranes. Conclusion: These findings suggest that the plasma ir-uroguanylin level is related to the patient’s volume status as well as renal impairment. Whether the accumulation of uroguanylin has a pathological effect has yet to be determined.

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