Renal effects of uroguanylin and guanylin in vivo

Uroguanylin and guanylin are newly discovered endogenous heat-stable peptid es that bind to and activate a membrane bound guanylyl cyclase signaling re ceptor (termed guanylyl cyclase C; GC-C). These peptides are not only found in blood but are secreted into the lumen of the intestine and effect a net secretion of electrolytes (Na+, K+, Cl-, HCO3-) and fluid into the intesti ne via a cyclic guanosine-3',5'-monophosphate (cGMP) mechanism. GC-C is als o the receptor for Escherichia coli heat-stable enterotoxin (STa) and activ ation by STa results in a diarrheal illness. Employing mouse renal in vivo models, we have demonstrated that uroguanylin, guanylin, and STa elicit nat riuretic, kaliuretic, and diuretic effects. These biological responses are time- and dose-dependent. Maximum natriuretic and kaliuretic effects are ob served within 30-40 min following infusion with pharmacological doses of th e peptides in a sealed-urethra mouse model. Our mouse renal clearance model confirms these results and shows significant natriuresis following a const ant infusion of uroguanylin for 30 min, while the glomerular filtration rat e, plasma creatinine, urine osmolality, heart rate, and blood pressure rema in constant. These data suggest the peptides act through tubular transport mechanisms. Consistent with a tubular mechanism, messenger RNA-differential display PCR of kidney RNA extracted from vehicle- and uroguanylin-treated mice show the message for the Na+/K+ ATPase gamma-subunit is down-regulated . Interestingly, GC-C knockout mice (Gucy2c -/-) also exhibit significant u roguanylin-induced natriuresis and kaliuresis in vivo, suggesting the prese nce of an alternate receptor signaling mechanism in the kidney. Thus, urogu anylin and guanylin seem to serve as intestinal and renal natriuretic pepti de-hormones influencing salt and water transport in the kidney through GC-C dependent and independent pathways. Furthermore, our recent clinical probe study has revealed a 70-fold increase in levels of urinary uroguanylin in patients with congestive heart failure. In conclusion, our studies support the concept that uroguanylin and guanylin are endogenous effector peptides involved in regulating body salt and water homeostasis.