Renal effects of uroguanylin and guanylin in vivo

Uroguanylin and guanylin are newly discovered endogenous heat-stable peptides that bind to and activate a membrane bound guanylyl cyclase signaling receptor (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 intestine via a cyclic guanosine-3',5'-monophosphate (cGMP) mechanism. GC-C is also the receptor for Escherichia coli heat-stable enterotoxin (STa) and activation by STa results in a diarrheal illness. Employing mouse renal in vivo models, we have demonstrated that uroguanylin, guanylin, and STa elicit natriuretic, kaliuretic, and diuretic effects. These biological responses are time- and dose-dependent. Maximum natriuretic and kaliuretic effects are observed within 30-40 min following infusion with pharmacological doses of the peptides in a sealed-urethra mouse model. Our mouse renal clearance model confirms these results and shows significant natriuresis following a constant infusion of uroguanylin for 30 min, while the glomerular filtration rate, plasma creatinine, urine osmolality, heart rate, and blood pressure remain 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 g-subunit is down-regulated. Interestingly, GC-C knockout mice (Gucy2c -/-) also exhibit significant uroguanylin-induced natriuresis and kaliuresis in vivo, suggesting the presence of an alternate receptor signaling mechanism in the kidney. Thus, uroguanylin and guanylin seem to serve as intestinal and renal natriuretic peptide-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.

Hemorrhagic Fevers : Few Clues after 25 Years

There is a high prevalence of Ebola antibodies found in the Kenya population; related to geographical area and season; although the clinical disease was never found and the virus was not isolated. A field study was carried out in 7 hospitals in western Kenya; 1986 -1987 (including surveillance studies in suspect areas); to intensify collection and transport of samples; testing facilities; patient observation with record keeping and follow-up. This study involved 1109 admitted patients with fever and/or bleeding; 155 contacts of haemorrahagic fever antibody (Hfab) patients; and 916 people in suspect areas. Respectively 160;44 and 80 persons were found Hfab positive mainly to Ebola; using an indirect immunofluorescent assay. From 676 viral cultures no virus was isolated. A relationship between antibody titres and ecological factors; social habitat; age; sex or season was not found. The non-specificity of IF testing was demonstrated by: 1) the disagreement between the results of two reference laboratories; 2) the unpredictability of the titre conversation course; and 3) by proving a significant cross-reactivity with Borrelia burgdorferii antibodies; Plasmodium falcparum antibodies and Salmonella typhi antibodies. Renewed testing in 1995 of 90 positive sera (with low titres) showed 19 sera to be positive by Elisa (2 in Zaire; 1 in Sudan; 9 in Reston and 7 in Cote d'Ivoire) from which 4 were confirmed by IFI 2 in Reston and 2 in Cote d'Ivoire. These findings are more proof that non-human virulent strains of Filoviridae; especially Ebola virus; are around in Kenya