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Leonard R Forte - One of the best experts on this subject based on the ideXlab platform.
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Printed in U.S.A. Copyright © 1999 by The Endocrine Society Lymphoguanylin: Cloning and Characterization of a Unique Member of the Guanylin Peptide Family
2013Co-Authors: Leonard R Forte, Ronald H. Freeman, Sammy L. Eber, David T. Chin, Xiaohui Fan, Yuan Wang, Roslyn M London, Linda M Rowland, William J. KrauseAbstract:Guanylin and Uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a Uroguanylin complementary DNA (cDNA) detected Uroguanylinlike messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than Uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84 % and 40 % of its residues with preproUroguanylin and preproguanylin, respectively. A 15-amino acid, Uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide produc
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REVIEW 4 uanylin: a peptide regulator of epithelial transport1
2013Co-Authors: Leonard R Forte, Mark Cur. C. RieAbstract:ABSTRACT Regulation of intestinal salt and water transport is critical to the maintenance of fluid volume. Control of this life-sustaining activity is mediated by the concerted actions of hormones, neurotransmitters, and locally acting factors, The intestinal peptide guanylin is ideally suited to play a pivotal role in this regulation. Guanylin is produced by the epithelium and appears to be secreted mucosally to act locally on an apical receptor. The guanylin receptor is a member of the guanylate cyclase (GC-C) family of proteins. Elevation of intracellular cyclic GMP by guanylin mediates the stimulation of C1 secretion, which results in the increased intestinal fluid secretion. Proguanylin is found in the circulation and GC-C occurs in other epithelia, suggesting that guanylin plays an endocrine role by regulating the function of tissues such as the kidney and liver. Uroguanylin is a structurally related peptide that is abundant in urine, has biological activity similar to guanylin, and appears to be made by the intestine. This peptide may link the intestine and kidney in an endocrine pathway for control of renal salt excretion. Overproduction of guanylin/Uroguanylin would be expected to elicit secretory diarrhea similar to that caused by the bacteria that produce peptide analogs of these endogenous peptide hormones. This unique molecular mimicry has provided clues leading to the discovery of guanylin and insight into the mechanism of action of these intestinal peptides. The discoveries of guanylin and Uroguanylin have provided exciting opportunities for further enhancing our understanding of epithelial transport and function.- Forte, L. R., Currie, M. C. Guanylin: a peptide regulator of epithelial transport
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in vivo imaging of human colorectal cancer using radiolabeled analogs of the Uroguanylin peptide hormone
Anticancer Research, 2009Co-Authors: Dijie Liu, Leonard R Forte, Douglas Overbey, Lisa D Watkinson, Said Daibesfigueroa, Timothy J Hoffman, Wynn A Volkert, Michael F GiblinAbstract:Background: Uroguanylin is an endogenous peptide agonist that binds to the guanylate cyclase C receptor (GC-C). GC-C is overexpressed in human colorectal cancer (CRC), and exposure of GC-C-expressing cells to GC-C agonists results in cell cycle arrest and/or apoptosis, highlighting the therapeutic potential of such compounds. This study describes the first use of radiolabeled Uroguanylin analogs for in vivo detection of CRC. Materials and Methods: The peptides Uroguanylin and E3-Uroguanylin were N-terminally labeled with the DOTA chelating group via NHS ester activation and characterized by RP-HPLC, ESI-MS, and GC-C receptor binding assays. The purified conjugates were radiolabeled with In-111 and used for in vivo biodistribution and SPECT imaging studies. In vivo experiments were carried out using SCID mice bearing T84 human colorectal cancer tumor xenografts. Results: Alteration of the position 3 aspartate residue to glutamate resulted in increased affinity for GC-C, with IC50 values of 5.0±0.3 and 9.6±2.9 nM for E3-Uroguanylin and DOTA-E3-Uroguanylin, respectively. In vivo, 111In-DOTA-E3-Uroguanylin demonstrated tumor uptake of 1.17±0.23 and 0.61±0.07% ID/g at 1 and 4 h post injection, respectively. The specificity of tumor localization was demonstrated by coinjection of 3 mg/kg unlabeled E3-Uroguanylin, which reduced tumor uptake by 69%. Uptake in kidney, however, was dramatically higher for the Uroguanylin peptides than for previously characterized radiolabeled E. coli heat-stable enterotoxin (STh) analogs targeting GC-C, and was also inhibited by coinjection of unlabeled peptide in a fashion not previously observed. Conclusion: Use of Uroguanylin-targeting vectors for in vivo imaging of colorectal cancers expressing GC-C resulted in tumor uptake that paralleled that of higher affinity heat-stable enterotoxin peptides, but also resulted in increased kidney uptake in vivo.
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interaction of atrial natriuretic peptide urodilatin guanylin and Uroguanylin in the isolated perfused rat kidney
Regulatory Peptides, 2006Co-Authors: M S Santosneto, Leonard R Forte, Helena Serra Azul Monteiro, Andre F Carvalho, M C FontelesAbstract:Escherichia coli heat-stable enterotoxin (STa), guanylin and Uroguanylin are novel natriuretic and kaliuretic peptides that bind to and activate membrane guanylate cyclase (GC) receptors such as GC-C and OK-GC that are expressed in the kidney and intestine. Atrial natriuretic peptide (ANP) and its renal form (urodilatin, UROD) elicit natriuretic effects by activation of a different membrane guanylate cyclase, GC-A. Experiments were done in perfused rat kidneys to search for possible synergistic interactions between ANP, UROD, guanylin and Uroguanylin on renal function. Pretreatment with ANP (0.03 nM) enhanced guanylin (0.19 microM) natriuretic activity (%ENa(+); from 18.5+/-4.25 to 31.5+/-1.69, P<0.05, 120 min) and its kaliuretic activity (%EK(+); from 24.5+/-4.43 to 50.6+/-3.84, P<0.05, 120 min). Furthermore, ANP increased the natriuretic (29.05+/-3.00 to 37.8+/-2.95, P<0.05, 120 min) and kaliuretic (from 33.2+/-3.52 to 42.83+/-2.45, P<0.05, 120 min) responses of perfused kidneys treated with low-dose (0.06 microM) Uroguanylin. In contrast, ANP clearly inhibited the Uroguanylin-induced (0.31 microM) increase in %ENa(+) (from 35.9+/-2.37 to 14.8+/-1.93, P<0.05, 120 min), and in %EK(+) (from 51.0+/-4.43 to 38.8+/-3.61, P<0.05, 120 min). UROD (0.03 nM) also enhanced the guanylin-induced natriuresis (to %ENa(+)=31.0+/-1.93, P<0.05, 120 min) and kaliuresis (to %EK(+)=54.2+/-3.61, P<0.05, 120 min), and inhibited the %ENa(+) of Uroguanylin (0.31 microM) to 17.9+/-1.67 as well as its %EK(+) to 24.3+/-3.13 (both at 120 min, P<0.05). The synergism between ANP and UROD with either guanylin or Uroguanylin at sub-threshold doses and the unexpected antagonism between ANP and UROD with Uroguanylin at a pharmacological dose point to possible interactions between natriuretic peptide receptor (NPR) and Uroguanylin/guanylin receptor signaling pathways. The interactions herein described may play a contributory role in the regulation of kidney function in many pathophysiological states, such as in the saliuresis following ingestion of salty meals.
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Uroguanylin and guanylin peptides: pharmacology and experimental therapeutics.
Pharmacology & therapeutics, 2004Co-Authors: Leonard R ForteAbstract:Guanylin, Uroguanylin, and the bacterial heat-stable enterotoxin (ST) peptides comprise a new family of cyclic guanosine 3'-5' monophosphate (cGMP)-regulating agonists. The discovery of guanylin and Uroguanylin peptides stems from studies of cellular mechanisms underlying a form of secretory diarrhea caused by enteric bacteria. Guanylin, Uroguanylin, and microbial ST peptides activate a common apical membrane receptor-guanylate cyclase (R-GC) that elicits large increases in the intestinal secretion of chloride and bicarbonate via the intracellular second messenger, cGMP. Guanylin and Uroguanylin were isolated from rat jejunum and opossum urine, respectively. These peptides are endogenous peptide hormones that physiologically regulate R-GC signaling proteins in target cells. Physiological roles for these peptides include the regulation of epithelial cell balance in the intestinal epithelium and modulation of sodium balance through actions in the kidney. The guanylin-Uroguanylin-ST peptides are candidate therapeutic agents targeting receptors in the intestine, kidney, and other epithelia. For example, Uroguanylin has anti-tumor actions in an animal model for human colon cancer. The ST peptides can be used as diagnostic agents to detect secondary colon cancers by single photon-emitting computed tomography (SPECT) imaging, thus localizing metastatic forms of colon cancer. Other examples of potential therapeutic applications for the guanylin family of cGMP-regulating agonists are: (1) the irritable bowel syndrome (IBS) with constipation, (2) salt-dependent forms of high blood pressure, (3) liver regeneration and repair, and (4) respiratory diseases such as asthma. Competitive pharmacological antagonists of bacterial ST peptides offer a means for treating the diarrhea caused by ST-secreting strains of enteric bacteria.
Sammy L. Eber - One of the best experts on this subject based on the ideXlab platform.
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Printed in U.S.A. Copyright © 1999 by The Endocrine Society Lymphoguanylin: Cloning and Characterization of a Unique Member of the Guanylin Peptide Family
2013Co-Authors: Leonard R Forte, Ronald H. Freeman, Sammy L. Eber, David T. Chin, Xiaohui Fan, Yuan Wang, Roslyn M London, Linda M Rowland, William J. KrauseAbstract:Guanylin and Uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a Uroguanylin complementary DNA (cDNA) detected Uroguanylinlike messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than Uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84 % and 40 % of its residues with preproUroguanylin and preproguanylin, respectively. A 15-amino acid, Uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide produc
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Printed in U.S.A. Copyright © 1997 by The Endocrine Society Signaling Pathways for Guanylin and Uroguanylin in the Digestive, Renal, Central Nervous, Reproductive, and Lymphoid Systems
2013Co-Authors: Xiaohui Fan, William J. Krause, Ronald H. Freeman, Sammy L. Eber, Yuan Wang, Roslyn M London, R. ForteAbstract:GUANYLIN and Uroguanylin are endogenous peptides that are similar to the heat-stable toxin (ST) peptides secreted by strains of enteric bacteria that cause secretory (traveler’s) diarrhea (1, 2). This family of small, cysteine-rich peptides activates membrane receptors that contain a guanylate cyclase (GC) catalytic domain within the cytoplasmic portion of the protein (3). One Uroguanylin/guanylin receptor-GC, GC-C, has been identified by molecular cloning of complementary DNAs (cDNAs) from intestinal cDNA libraries (4, 5). This cell surface receptor-GC belongs to an emerging family of signaling molecules, including the receptors for atriopeptins (3). GC-C is unique because this protein is localized to apical plasma membranes of cells in the intestinal mucosa, renal tubules, and other epithelia (6–9). Localization of receptor-GCs on the mucosal surface of epithelial cells implies that regulation of GC activity occurs via paracrine and/or autocrine mechanisms. The binding of Uroguanylin, guanylin, or ST to GC-C enhances the production and intracellular accumulation of cGMP, which in the intestinal epithelium results in stimulation of transepithelial chloride and bicarbonate secretion into the intestinal lumen (1, 2, 10–12). A molecular target for cGMP-stimulated protein kinases is the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which may regulate the activity of other anion channels and/or serve to conduct chlorid
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Uroguanylin treatment suppresses polyp formation in the apcmin mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic gmp
Cancer Research, 2000Co-Authors: Kunwar Shailubhai, Sammy L. Eber, Helen Yu, Kanthasamy Karunanandaa, Joan Y Wang, Yuan Wang, Brent W Miedema, Zaheer S Abbas, Sekhar S Boddupalli, Mark G. CurrieAbstract:The enteric peptides, guanylin and Uroguanylin, are local regulators of intestinal secretion by activation of receptor-guanylate cyclase (R-GC) signaling molecules that produce cyclic GMP (cGMP) and stimulate the cystic fibrosis transmembrane conductance regulator-dependent secretion of Cl− and HCO3−. Our experiments demonstrate that mRNA transcripts for guanylin and Uroguanylin are markedly reduced in colon polyps and adenocarcinomas. In contrast, a specific Uroguanylin-R-GC, R-GCC, is expressed in polyps and adenocarcinomas at levels comparable with normal colon mucosa. Activation of R-GCC by Uroguanylin in vitro inhibits the proliferation of T84 colon cells and elicits profound apoptosis in human colon cancer cells, T84. Therefore, down-regulation of gene expression and loss of the peptides may interfere with renewal and/or removal of the epithelial cells resulting in the formation of polyps, which can progress to malignant cancers of the colon and rectum. Oral replacement therapy with human Uroguanylin was used to evaluate its effects on the formation of intestinal polyps in the Min/+ mouse model for colorectal cancer. Uroguanylin significantly reduces the number of polyps found in the intestine of Min/+ mice by ∼50% of control. Our findings suggest that Uroguanylin and guanylin regulate the turnover of epithelial cells within the intestinal mucosa via activation of a cGMP signaling mechanism that elicits apoptosis of target enterocytes. The intestinal R-GC signaling molecules for guanylin regulatory peptides are promising targets for prevention and/or therapeutic treatment of intestinal polyps and cancers by oral administration of human Uroguanylin.
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increased urinary excretion of Uroguanylin in patients with congestive heart failure
American Journal of Physiology-heart and Circulatory Physiology, 2000Co-Authors: Leonard R Forte, Sammy L. Eber, Stephen L Carrithers, Richard N GreenbergAbstract:Uroguanylin is a small-molecular-weight peptide that activates membrane-bound receptor-guanylate cyclases in the intestine, kidney, and other epithelia. Uroguanylin has been shown to participate in...
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lymphoguanylin cloning and characterization of a unique member of the guanylin peptide family
Endocrinology, 1999Co-Authors: Leonard R Forte, Sammy L. Eber, David T. Chin, Xiaohui Fan, R H Freeman, Yuan Wang, Roslyn M London, Linda M Rowland, William J. KrauseAbstract:Guanylin and Uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a Uroguanylin complementary DNA (cDNA) detected Uroguanylin-like messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than Uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84% and 40% of its residues with preproUroguanylin and preproguanylin, respectively. A 15-amino acid, Uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide product lymphoguanylin because the source of the first cDNA isolated was spleen and its mRNA is expressed in all of the lymphoid tissues tested. A 15-amino acid form of lymphoguanylin containing a single disulfide bond was synthesized that activates the guanylate cyclase receptors of human T84 intestinal and opossum kidney (OK) cells, although with less potency than Uroguanylin and guanylin. Northern and/or RT-PCR assays detected lymphoguanylin mRNA transcripts in many tissues and organs of opossums, including those within the lymphoid/immune, cardiovascular/renal, reproductive, and central nervous organ systems. Lymphoguanylin joins guanylin and Uroguanylin in a growing family of peptide agonists that activate transmembrane guanylate cyclase receptors, thus influencing target cell function via the intracellular second messenger, cGMP.
Masamitsu Nakazato - One of the best experts on this subject based on the ideXlab platform.
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Printed in U.S.A. Copyright © 1998 by The Endocrine Society Tissue Distribution, Cellular Source, and Structural Analysis of Rat Immunoreactive Uroguanylin*
2013Co-Authors: Masamitsu Nakazato, Michael F Goy, Hideki Yamaguchi, Yukari Date, Mikiya Miyazato, Kenji Kangawa, Naoyoshi ChinoAbstract:Uroguanylin, a member of the guanylin peptide family, acts on guanylyl cyclase C (GC-C) to regulate intestinal and renal fluid and electrolyte transport through the second messenger, cGMP. Using an antiserum raised against synthetic rat Uroguanylin, we established an RIA and identified three endogenous molecular forms in the intestine and kidney: a 15-amino acid Uroguanylin, an 18-amino acid Uroguanylin that is a monobasic processing product, and a 9.4-kDa proUroguanylin. ProUroguanylin is the major molecular form in these two tissues, whereas only 15-amino-acid Uroguanylin is present in the GUANYLIN and Uroguanylin are novel peptide regulators of intestinal, and possibly renal, salt and water transport (1–6). These two peptides consist of 15–16 amino acids and have a conserved backbone of two disulfide bridges that are essential for their biological activities. The
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role of Uroguanylin a peptide with natriuretic activity in rats with experimental nephrotic syndrome
Journal of The American Society of Nephrology, 2005Co-Authors: Masao Kikuchi, Shouichi Fujimoto, Hiroko Fukae, Hiroshi Kinoshita, Toshihiro Kita, Masamitsu Nakazato, Tanenao EtoAbstract:Uroguanylin induces natriuresis and diuresis in vivo as well as in vitro and is found mainly in the intestine and the kidney. However, the roles of Uroguanylin in nephrotic syndrome, which is associated with sodium and water retention, have not been determined. Therefore, changes in the urine and plasma concentration of immunoreactive Uroguanylin (ir-Uroguanylin) and its mRNA expression in the kidney and intestine were examined using rats with puromycin aminonucleoside (PAN)-induced nephrosis. Male Sprague-Dawley rats were separated into control and nephrotic groups, and then the urinary excretion of sodium, protein, and ir-Uroguanylin was examined over time. The plasma levels and renal and intestinal mRNA expression of Uroguanylin at the periods of sodium retention and remarkable natriuresis also were evaluated. The sequential changes of urinary ir-Uroguanylin excretion in the nephrotic group were similar to those of urinary sodium excretion. When the urinary excretion of ir-Uroguanylin and sodium peaked, the plasma level of ir-Uroguanylin also increased compared with that of the control group. Uroguanylin mRNA expression in the kidney increased during the period of sodium retention and then decreased during the period of remarkable natriuresis. Uroguanylin mRNA expression in the small intestines of control and nephrotic rats were identical. However, in a unilateral PAN-induced proteinuria, Uroguanylin expression significantly increased in the PAN-perfused kidney compared with that in the opposite kidney. Considering the natriuretic effect of Uroguanylin, these results suggested that Uroguanylin plays an important role as a natriuretic factor in nephrotic syndrome via both the circulation and the kidney itself.
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changes in urinary levels and renal expression of Uroguanylin on low or high salt diets in rats
Nephron, 2002Co-Authors: Hiroko Fukae, Shouichi Fujimoto, Hiroshi Kinoshita, Toshihiro Kita, Masamitsu Nakazato, Tanenao EtoAbstract:Background: The novel peptide, Uroguanylin, is mainly produced in the intestine and causes natriuresis via cyclic GMP (cGMP) activation. Uroguanylin plays an important role in sodium transport in the gastrointestinal tract and functions as an intestinal natriuretic hormone during oral salt load. However, the role and behavior of Uroguanylin in the kidneys during high salt load remains unknown. Methods: We measured the Uroguanylin concentrations in the urine and plasma of rats fed with low or high salt diets for 1 week, using a sensitive radioimmunoassay (RIA). Urinary cGMP and electrolyte excretion was also measured. Intestinal and renal expression of Uroguanylin mRNA was evaluated by Northern blotting and by reverse transcription-polymerase chain reaction (RT-PCR). Results: The urinary excretion of immunoreactive (ir-) Uroguanylin in rats on the high salt diet was significantly higher than that in the low salt group (425 ± 107 vs. 128 ± 8.5 pmol/day, p + and cGMP excretion. Plasma ir-Uroguanylin levels between the two groups did not significantly differ. Uroguanylin mRNA expression was increased both in the intestine and kidneys of rats on the high salt diet. Conclusion: These findings suggest that Uroguanylin regulates sodium metabolism in the intestine and kidneys during oral salt load in an autocrine and paracrine manner.
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Uroguanylin level in umbilical cord blood
Pediatrics International, 2001Co-Authors: Hirokazu Tsukahara, Masamitsu Nakazato, Yukari Date, Kyoichi Sekine, Mayumi Uchiyama, Masakazu Miura, Wataru Tsunezawa, Fumikazu Kotsuji, Koichi Nishida, Masahiro HiraokaAbstract:Background: Uroguanylin is a novel natriuretic and diuretic peptide originally isolated from urine. Methods: To determine whether Uroguanylin has a physiologic role during the perinatal period, Uroguanylin levels in umbilical cord plasma obtained at the time of delivery were measured by radioimmunoassay and compared with cord serum osmolality. Results: Mean (±SD) cord plasma Uroguanylin concentrations (8.8±2.1 fmol/mL) were higher compared with normal adult values. The extent of maturity, mode of delivery and gender did not appear to influence cord Uroguanylin levels. The Uroguanylin concentration had a significant positive correlation with cord serum osmolality. Conclusion: These findings support some regulatory role of this peptide in perinatal renal and cardiovascular adaptation.
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plasma concentration of Uroguanylin in patients on maintenance dialysis therapy
Nephron, 2000Co-Authors: Hiroko Fukae, Shouichi Fujimoto, Hiroshi Kinoshita, Masamitsu Nakazato, Tanenao EtoAbstract:Background: Uroguanylin, originally isolated from urine, is a new natriuretic peptide. Its plasma level is increased in association with renal impairment and fluid retention in patients with renal diseases. Methods: Uroguanylin concentrations were measured in patients on hemodialysis (HD, n = 76) and those on continuous ambulatory peritoneal dialysis (CAPD, n = 10) using a sensitive ra- dioimmunoassay for human Uroguanylin. Results: Plasma concentrations of immunoreactive (ir)-Uroguanylin in the patients on HD and CAPD (212.0 ± 17.4 and 245.3 ± 39.5 fmol/ml) were significantly higher than the value for the normal controls (5.0 ± 0.3 fmol/ml). Plasma ir-Uroguanylin levels before the start of regular HD were correlated with predialysis excess weight based on their dry weights (r = 0.33, p Conclusion: These findings suggest that the plasma ir-Uroguanylin level is related to the patient’s volume status as well as renal impairment. Whether the accumulation of Uroguanylin has a pathological effect has yet to be determined.
R H Freeman - One of the best experts on this subject based on the ideXlab platform.
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lymphoguanylin cloning and characterization of a unique member of the guanylin peptide family
Endocrinology, 1999Co-Authors: Leonard R Forte, Sammy L. Eber, David T. Chin, Xiaohui Fan, R H Freeman, Yuan Wang, Roslyn M London, Linda M Rowland, William J. KrauseAbstract:Guanylin and Uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a Uroguanylin complementary DNA (cDNA) detected Uroguanylin-like messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than Uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84% and 40% of its residues with preproUroguanylin and preproguanylin, respectively. A 15-amino acid, Uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide product lymphoguanylin because the source of the first cDNA isolated was spleen and its mRNA is expressed in all of the lymphoid tissues tested. A 15-amino acid form of lymphoguanylin containing a single disulfide bond was synthesized that activates the guanylate cyclase receptors of human T84 intestinal and opossum kidney (OK) cells, although with less potency than Uroguanylin and guanylin. Northern and/or RT-PCR assays detected lymphoguanylin mRNA transcripts in many tissues and organs of opossums, including those within the lymphoid/immune, cardiovascular/renal, reproductive, and central nervous organ systems. Lymphoguanylin joins guanylin and Uroguanylin in a growing family of peptide agonists that activate transmembrane guanylate cyclase receptors, thus influencing target cell function via the intracellular second messenger, cGMP.
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structure and activity of Uroguanylin and guanylin from the intestine and urine of rats
American Journal of Physiology-endocrinology and Metabolism, 1997Co-Authors: Xiaohui Fan, William J. Krause, Sammy L. Eber, Mark G. Currie, Christine E. Smith, Kent F Hamra, R H Freeman, Roslyn M London, Leonard R ForteAbstract:Uroguanylin and guanylin are related peptides that activate common guanylate cyclase signaling molecules in the intestine and kidney. Uroguanylin was isolated from urine and duodenum but was not de...
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signaling pathways for guanylin and Uroguanylin in the digestive renal central nervous reproductive and lymphoid systems
Endocrinology, 1997Co-Authors: William J. Krause, Sammy L. Eber, Xiaohui Fan, Yuan Wang, Roslyn M London, R H FreemanAbstract:Guanylin and Uroguanylin are peptides that stimulate membrane guanylate cyclases (GC) and regulate intestinal and renal function via cGMP. Complementary DNAs were isolated encoding opossum preproguanylin and a 279-amino acid portion of a receptor-guanylate cyclase expressed in opossum kidney (OK) cells (GC-OK). The tissue expression of messenger RNA transcripts for these signaling molecules were then compared. Northern and/or reverse transcription-PCR assays revealed that guanylin, Uroguanylin, and GC-OK messenger RNAs are expressed in tissues within the digestive, renal, central nervous, reproductive, and lymphoid organ systems. Receptor autoradiography localized the receptors for Uroguanylin and guanylin to renal proximal tubules and seminiferous tubules of testis. Synthetic guanylin and Uroguanylin peptides activated the receptor-GCs in opossum kidney cortex and in cultured OK cells eliciting increased intracellular cGMP. Expression of agonist and receptor-GC signaling molecules provides a pathway for paracrine and/or autocrine regulation of cellular functions via cGMP in the digestive, renal, central nervous, reproductive, and lymphoid/immune organ systems. Uroguanylin also links the intestine and kidney in a potential endocrine axis that activates tubular receptor-GCs and influences renal function.
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Uroguanylin cloning of preproUroguanylin cdna mrna expression in the intestine and heart and isolation of Uroguanylin and proUroguanylin from plasma
Biochemical and Biophysical Research Communications, 1996Co-Authors: Xiaohui Fan, William J. Krause, Sammy L. Eber, Mark G. Currie, Kent F Hamra, R H Freeman, Robert W Lim, Victor M Pace, Leonard R ForteAbstract:Uroguanylin is a small peptide isolated from opossum urine that activates membrane guanylate cyclases. We report the isolation by molecular cloning of cDNAs encoding the 109 amino acid preproUroguanylin containing the active Uroguanylin peptide at its C-terminus. PreproUroguanylin mRNAs of 1.2 kb were detected throughout the small and large intestine and in the atria and ventricles of heart, but not in kidney, stomach or liver. Transfection of COS-1 cells with the Uroguanylin cDNA resulted in proUroguanylin secretion. Both Uroguanylin and proUroguanylin were isolated from opossum plasma. Thus, Uroguanylin is made by the intestine and heart and circulates as a bioactive form of Uroguanylin and the inactive proUroguanylin.
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distribution of escherichia coli heat stable enterotoxin guanylin Uroguanylin receptors in the avian intestinal tract
Cells Tissues Organs, 1995Co-Authors: William J. Krause, Sammy L. Eber, F K Hamra, R H Freeman, K F Fok, M G Currie, Leonard R ForteAbstract:Pathogenic strains of enteric bacteria secrete small heat-stable toxins (STs) that activate membrane guanylyl cyclase receptors found in the intestine. The intestinal peptide agonists, guanylin and Uroguanylin, are structurally related to STs. Receptors for 125I-ST were found throughout the entire length of the intestinal tract of all the birds examined. These receptors were restricted to intestinal epithelial cells covering villi and forming intestinal glands and were not observed in other strata of the gut wall. The most intense labeling of receptors by 125I-ST occurred in the region of the microvillus border of individual enterocytes. There appeared to be a decrease in receptor density distally along the length of the small intestine, although labeling of receptors by 125I-ST was observed throughout the small intestine and colon. Cellular cGMP accumulation responses to Escherichia coli ST and rat guanylin in the domestic turkey and duck were greater in the proximal small intestine compared to the distal small intestine or colon. Brush border membranes (BBM) isolated from the mucosa of proximal small intestine of turkeys exhibited agonist-stimulated guanylyl cyclase activity. The rank order potency for enzyme activation was E. coli ST > Uroguanylin > guanylin. Competitive radioligand binding assays using 125I-ST and turkey intestine BBM revealed a similar rank order affinity for the receptors that was exemplified by the Kd values of ST 2.5 nM, Uroguanylin 80 nM and guanylin 2.6 microM. It may be concluded that functional receptors for the endogenous peptides, guanylin and Uroguanylin, occur in the apical membranes of enterocytes throughout the avian intestine. The receptor-guanylyl cyclase(s) of proximal small intestine were preferentially activated by Uroguanylin relative to guanylin, but both endogenous peptides were less potent than their molecular mimic, E. coli ST.
Xiaohui Fan - One of the best experts on this subject based on the ideXlab platform.
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Printed in U.S.A. Copyright © 1999 by The Endocrine Society Lymphoguanylin: Cloning and Characterization of a Unique Member of the Guanylin Peptide Family
2013Co-Authors: Leonard R Forte, Ronald H. Freeman, Sammy L. Eber, David T. Chin, Xiaohui Fan, Yuan Wang, Roslyn M London, Linda M Rowland, William J. KrauseAbstract:Guanylin and Uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a Uroguanylin complementary DNA (cDNA) detected Uroguanylinlike messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than Uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84 % and 40 % of its residues with preproUroguanylin and preproguanylin, respectively. A 15-amino acid, Uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide produc
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Printed in U.S.A. Copyright © 1997 by The Endocrine Society Signaling Pathways for Guanylin and Uroguanylin in the Digestive, Renal, Central Nervous, Reproductive, and Lymphoid Systems
2013Co-Authors: Xiaohui Fan, William J. Krause, Ronald H. Freeman, Sammy L. Eber, Yuan Wang, Roslyn M London, R. ForteAbstract:GUANYLIN and Uroguanylin are endogenous peptides that are similar to the heat-stable toxin (ST) peptides secreted by strains of enteric bacteria that cause secretory (traveler’s) diarrhea (1, 2). This family of small, cysteine-rich peptides activates membrane receptors that contain a guanylate cyclase (GC) catalytic domain within the cytoplasmic portion of the protein (3). One Uroguanylin/guanylin receptor-GC, GC-C, has been identified by molecular cloning of complementary DNAs (cDNAs) from intestinal cDNA libraries (4, 5). This cell surface receptor-GC belongs to an emerging family of signaling molecules, including the receptors for atriopeptins (3). GC-C is unique because this protein is localized to apical plasma membranes of cells in the intestinal mucosa, renal tubules, and other epithelia (6–9). Localization of receptor-GCs on the mucosal surface of epithelial cells implies that regulation of GC activity occurs via paracrine and/or autocrine mechanisms. The binding of Uroguanylin, guanylin, or ST to GC-C enhances the production and intracellular accumulation of cGMP, which in the intestinal epithelium results in stimulation of transepithelial chloride and bicarbonate secretion into the intestinal lumen (1, 2, 10–12). A molecular target for cGMP-stimulated protein kinases is the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which may regulate the activity of other anion channels and/or serve to conduct chlorid
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lymphoguanylin cloning and characterization of a unique member of the guanylin peptide family
Endocrinology, 1999Co-Authors: Leonard R Forte, Sammy L. Eber, David T. Chin, Xiaohui Fan, R H Freeman, Yuan Wang, Roslyn M London, Linda M Rowland, William J. KrauseAbstract:Guanylin and Uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a Uroguanylin complementary DNA (cDNA) detected Uroguanylin-like messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than Uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84% and 40% of its residues with preproUroguanylin and preproguanylin, respectively. A 15-amino acid, Uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide product lymphoguanylin because the source of the first cDNA isolated was spleen and its mRNA is expressed in all of the lymphoid tissues tested. A 15-amino acid form of lymphoguanylin containing a single disulfide bond was synthesized that activates the guanylate cyclase receptors of human T84 intestinal and opossum kidney (OK) cells, although with less potency than Uroguanylin and guanylin. Northern and/or RT-PCR assays detected lymphoguanylin mRNA transcripts in many tissues and organs of opossums, including those within the lymphoid/immune, cardiovascular/renal, reproductive, and central nervous organ systems. Lymphoguanylin joins guanylin and Uroguanylin in a growing family of peptide agonists that activate transmembrane guanylate cyclase receptors, thus influencing target cell function via the intracellular second messenger, cGMP.
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structure and activity of Uroguanylin and guanylin from the intestine and urine of rats
American Journal of Physiology-endocrinology and Metabolism, 1997Co-Authors: Xiaohui Fan, William J. Krause, Sammy L. Eber, Mark G. Currie, Christine E. Smith, Kent F Hamra, R H Freeman, Roslyn M London, Leonard R ForteAbstract:Uroguanylin and guanylin are related peptides that activate common guanylate cyclase signaling molecules in the intestine and kidney. Uroguanylin was isolated from urine and duodenum but was not de...
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signaling pathways for guanylin and Uroguanylin in the digestive renal central nervous reproductive and lymphoid systems
Endocrinology, 1997Co-Authors: William J. Krause, Sammy L. Eber, Xiaohui Fan, Yuan Wang, Roslyn M London, R H FreemanAbstract:Guanylin and Uroguanylin are peptides that stimulate membrane guanylate cyclases (GC) and regulate intestinal and renal function via cGMP. Complementary DNAs were isolated encoding opossum preproguanylin and a 279-amino acid portion of a receptor-guanylate cyclase expressed in opossum kidney (OK) cells (GC-OK). The tissue expression of messenger RNA transcripts for these signaling molecules were then compared. Northern and/or reverse transcription-PCR assays revealed that guanylin, Uroguanylin, and GC-OK messenger RNAs are expressed in tissues within the digestive, renal, central nervous, reproductive, and lymphoid organ systems. Receptor autoradiography localized the receptors for Uroguanylin and guanylin to renal proximal tubules and seminiferous tubules of testis. Synthetic guanylin and Uroguanylin peptides activated the receptor-GCs in opossum kidney cortex and in cultured OK cells eliciting increased intracellular cGMP. Expression of agonist and receptor-GC signaling molecules provides a pathway for paracrine and/or autocrine regulation of cellular functions via cGMP in the digestive, renal, central nervous, reproductive, and lymphoid/immune organ systems. Uroguanylin also links the intestine and kidney in a potential endocrine axis that activates tubular receptor-GCs and influences renal function.
