Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load.
Guanylin and uroguanylin, peptides synthesized in the intestine and kidney, have been 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 uroguanylin in the regulation of sodium excretion, we created gene-targeted mice in which uroguanylin gene expression had been ablated. Northern and Western analysis confirmed the absence of uroguanylin message and protein in knockout mice, and cGMP levels were decreased in the mucosa of the small intestine. Ussing chamber analysis of jejunum revealed that Na+/H+ exchanger-mediated Na+ absorption and tissue conductance was not altered in the knockout animals, but short-circuit current, an index of electrogenic anion secretion, was reduced. Renal clearance measurements showed that uroguanylin deficiency results in impaired ability to excrete an enteral load of NaCl, primarily due to an inappropriate increase in renal Na+ reabsorption. Finally, telemetric recordings of blood pressure demonstrated increased mean arterial pressure in uroguanylin knockout animals that was independent of the level of dietary salt intake. Together, these findings establish a role for uroguanylin in an enteric-renal communication axis as well as a fundamental principle of this axis in the maintenance of salt homeostasis in vivo.
Lorenz
John N
JN
Department of Molecular and Cellular Physiology, University of Cincinnati, School of Medicine, Cincinnati, Ohio 45267-0576, USA. john.lorenz@uc.edu
Nieman
Michelle
M
Sabo
Jenine
J
Sanford
L Philip
LP
Hawkins
Jennifer A
JA
Elitsur
Noeet
N
Gawenis
Lara R
LR
Clarke
Lane L
LL
Cohen
Mitchell B
MB
D000818:Animals; D001794:Blood Pressure; D006152:Cyclic GMP / Q000032:analysis; D005838:Genotype; D007583:Jejunum / Q000378:metabolism; D007668:Kidney / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009318:Natriuresis; D045265:Natriuretic Peptides; D010455:Peptides / Q000502:physiology*; D012965:Sodium Chloride / Q000378:metabolism*
D045265:Natriuretic Peptides; D010455:Peptides; C084362:uroguanylin; D012965:Sodium Chloride; D006152:Cyclic GMP