TY - JOUR
T1 - Salt and water homeostasis
T2 - Uroguanylin is a circulating peptide hormone with natriuretic activity
AU - Forte, Leonard R.
AU - Fan, Xiaohui
AU - Hamra, F. Kent
N1 - Funding Information:
From the Medical Research Service, Harry S. Truman VA Medical Center and Department of Pharmacology, Missouri University School of Medicine, Columbia, MO. Received December 22, 1995; accepted in revised form March 19, 1996. Supported by the Medical Research Service, United States Department of Veterans Affairs, Washington, DC. Address reprint requests to Leonard R. Forte, PhD, Professor of Pharmacology and V.A. Research Career Scientist, M-515 Medical Sciences Building, Missouri University School of Medicine, Columbia, MO 65212. 0 1996 by the National Kidney Foundation, 0272-638tW6/2802-0022$3.00/O
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1996/8
Y1 - 1996/8
N2 - Guanylin and uroguanylin are small, heat-stable peptides that were initially isolated from rat jejunum and opossum urine, respectively. Both peptides bind to and activate a common set of apical membrane receptors that contain a guanylate cyclase catalytic domain within the receptor molecule. The guanylin/uroguanylin receptors are found on the luminal surface of epithelial cells lining the intestinal tract and renal proximal tubules as well as in other organs. Activation of receptor-guanylate cyclase signaling molecules by uroguanylin or guanylin elicits large increases in guanosine cyclic 3'-5' monophosphate (cGMP) production. Intracellular accumulation of this second messenger in target cells leads to the stimulation of intestinal chloride secretion, culminating in the enhancement of salt and water secretion into the intestinal lumen as well as increases in urinary sodium, potassium, and water excretion by actions of cGMP in the renal tubules. Uroguanylin and guanylin are produced throughout the intestinal mucosa and, surprisingly, uroguanylin messenger RNA (mRNA) is also expressed in both atria and ventricles of the heart. Both proguanylin and prouroguanylin are inactive polypeptides, and activation is accomplished by cleavage and release of the COOH-terminal peptides, guanylin and uroguanylin. Uroguanylin is postulated to function as an intestinal natriuretic hormone because: (1) prouroguanylin and uroguanylin both circulate in the plasma of normal animals; (2) uroguanylin is the predominant peptide agonist appearing in the filtrate and, thus, in urine; (3) the receptors for uroguanylin are localized to the apical membranes of renal tubular cells; (4) uroguanylin is substantially more potent than guanylin in eliciting a natriuresis; and (5) uroguanylin is expressed in the duodenum and myocardium, which are appropriate sites in the body for the production and release of a hormone that acts as a natriuretic agonist in vivo. The hypothesis that uroguanylin links the intestine with the kidney in an endocrine axis also predicts that the secretion of uroguanylin from the intestinal mucosa will be influenced by dietary levels of salt. Accordingly, plasma levels of uroguanylin or prouroguanylin should be influenced by oral salt loads. Future investigations will focus on the basic endocrinology of uroguanylin to provide answers to this intriguing question. In conclusion, uroguanylin is a candidate for a physiological role as an intestinal natriuretic hormone. Key features of the biology of uroguanylin provide a putative explanation for the substantial natriuresis that occurs in human subjects and experimental animals after an oral salt load. Moreover, uroguanylin and guanylin participate cooperatively in an intrinsic pathway for regulation of intestinal salt and water transport, thus providing another means of influencing salt and water homeostasis in addition to the renal actions of uroguanylin.
AB - Guanylin and uroguanylin are small, heat-stable peptides that were initially isolated from rat jejunum and opossum urine, respectively. Both peptides bind to and activate a common set of apical membrane receptors that contain a guanylate cyclase catalytic domain within the receptor molecule. The guanylin/uroguanylin receptors are found on the luminal surface of epithelial cells lining the intestinal tract and renal proximal tubules as well as in other organs. Activation of receptor-guanylate cyclase signaling molecules by uroguanylin or guanylin elicits large increases in guanosine cyclic 3'-5' monophosphate (cGMP) production. Intracellular accumulation of this second messenger in target cells leads to the stimulation of intestinal chloride secretion, culminating in the enhancement of salt and water secretion into the intestinal lumen as well as increases in urinary sodium, potassium, and water excretion by actions of cGMP in the renal tubules. Uroguanylin and guanylin are produced throughout the intestinal mucosa and, surprisingly, uroguanylin messenger RNA (mRNA) is also expressed in both atria and ventricles of the heart. Both proguanylin and prouroguanylin are inactive polypeptides, and activation is accomplished by cleavage and release of the COOH-terminal peptides, guanylin and uroguanylin. Uroguanylin is postulated to function as an intestinal natriuretic hormone because: (1) prouroguanylin and uroguanylin both circulate in the plasma of normal animals; (2) uroguanylin is the predominant peptide agonist appearing in the filtrate and, thus, in urine; (3) the receptors for uroguanylin are localized to the apical membranes of renal tubular cells; (4) uroguanylin is substantially more potent than guanylin in eliciting a natriuresis; and (5) uroguanylin is expressed in the duodenum and myocardium, which are appropriate sites in the body for the production and release of a hormone that acts as a natriuretic agonist in vivo. The hypothesis that uroguanylin links the intestine with the kidney in an endocrine axis also predicts that the secretion of uroguanylin from the intestinal mucosa will be influenced by dietary levels of salt. Accordingly, plasma levels of uroguanylin or prouroguanylin should be influenced by oral salt loads. Future investigations will focus on the basic endocrinology of uroguanylin to provide answers to this intriguing question. In conclusion, uroguanylin is a candidate for a physiological role as an intestinal natriuretic hormone. Key features of the biology of uroguanylin provide a putative explanation for the substantial natriuresis that occurs in human subjects and experimental animals after an oral salt load. Moreover, uroguanylin and guanylin participate cooperatively in an intrinsic pathway for regulation of intestinal salt and water transport, thus providing another means of influencing salt and water homeostasis in addition to the renal actions of uroguanylin.
KW - Uroguanylin
KW - cGMP
KW - guanylate cyclase
KW - intestine
KW - kidney
KW - salt homeostasis
UR - http://www.scopus.com/inward/record.url?scp=0029821322&partnerID=8YFLogxK
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U2 - 10.1016/S0272-6386(96)90318-2
DO - 10.1016/S0272-6386(96)90318-2
M3 - Article
C2 - 8768930
AN - SCOPUS:0029821322
SN - 0272-6386
VL - 28
SP - 296
EP - 304
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 2
ER -