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. 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). 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. These findings suggest that uroguanylin regulates sodium metabolism in the intestine and kidneys during oral salt load in an autocrine and paracrine manner.