The proximal convoluted tubule is a target for the uroguanylin-regulated natriuretic response.
OBJECTIVE
Guanylin and uroguanylin are peptides synthesized in the intestine and kidney that are postulated to have both paracrine and endocrine functions, forming a potential enteric-renal link to coordinate salt ingestion with natriuresis. To explore the in vivo role of guanylin and uroguanylin in the regulation of sodium excretion, we used gene-targeted mice in which the uroguanylin, guanylin or the peptide receptor guanylate cyclase C gene expression had been ablated.


RESULTS
Metabolic balance studies demonstrated that there was impaired excretion of a sodium load in uroguanylin (but not in guanylin or guanylate cyclase C) knockout mice. Uroguanylin-dependent natriuresis occurred without an increase in circulating prouroguanylin. A distinct morphological phenotype was present in the proximal convoluted tubules of uroguanylin knockout animals after an enteral salt loading. Marked vacuolization of the proximal convoluted tubule epithelial cells was observed by using light and electron microscopy. There was also a change in the distribution of the sodium hydrogen exchanger 3 (NHE3) after an enteral salt loading. In wild-type animals, there was a partial redistribution of NHE3 from the villus fraction to the less accessible submicrovillus membrane compartment, but this effect was less apparent in uroguanylin knockout animals, presumably resulting in greater Na/H exchange.


CONCLUSIONS
Together, these findings further establish a role for uroguanylin in fluid homeostasis and support a role for uroguanylin as an integral component of a signaling mechanism that mediates changes in Na excretion in response to an enteral salt loading. Proximal tubular NHE3 activity is a possible target for uroguanylin-mediated changes in Na excretion.
Elitsur
Noeet
N
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati, OH 45229, USA.
Lorenz
John N
JN
Hawkins
Jennifer A
JA
Rudolph
Jeffrey A
JA
Witte
David
D
Yang
Li E
LE
McDonough
Alicia A
AA
Cohen
Mitchell B
MB
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015153:Blotting, Western; D006152:Cyclic GMP / Q000652:urine; D004750:Enteral Nutrition; D019084:Fluorescent Antibody Technique, Indirect; D005768:Gastrointestinal Hormones / Q000097:blood / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D023421:Models, Animal; D009318:Natriuresis / Q000187:drug effects; D045265:Natriuretic Peptides / Q000097:blood / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000187:drug effects / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014882:Water-Electrolyte Balance / Q000187:drug effects
D015415:Biomarkers; D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D015221:Potassium Channels; D018000:Receptors, Peptide; C000613386:Slc9a3 protein, mouse; D017673:Sodium Chloride, Dietary; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C072685:guanylin; C084362:uroguanylin; D006162:Guanylate Cyclase; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP