Role of Uroguanylin, a Peptide with Natriuretic Activity, in Rats with Experimental Nephrotic Syndrome

Abstract

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...

Uroguanylin, an Intestinal Natriuretic Peptide, Is Delivered to the Kidney as an Unprocessed Propeptide

“…In fact, the percentage is probably much lower because sensitive RIA measurements have established a circulating level of 0.003 pmol/ml for UGn in human plasma (50). Note that the published assays of UGn levels in rat plasma report only "total UGn-like" immunoreactivity, without separating UGn from proUGn (35,36); see the Discussion for further elaboration of this point.…”

Current Understanding of Guanylin Peptides Actions

“…In patients with nephritic syndrome, UGN plasma concentration was higher and urinary concentration was lower compared with values in healthy volunteers possibly because kidney is damaged and it has reduced capability to metabolize and excrete GPs [40]. Recently, in experimental nephrotic syndrome, changes in UGN concentrations in urine and plasma corresponded to changes in Na + excretion; therefore, UGN could be used as natriuretic peptide in nephritic syndrome [149, 150]. …”

Pendrin, a Novel Transcriptional Target of the Uroguanylin System

“…It is noteworthy, in this regard, that patients with chronic renal failure [21, 90], glomerulonephritis [22] and nephrotic syndrome [22] display increased plasma levels of guanylin peptides. In some of these disease states, such as in nephrotic syndrome [22, 91], UGN may be mobilized to act as a natriuretic factor.…”