1 Clinical Research Unit of Federal University of Ceara and Ceara State University, 60434 Fortaleza-CE, Brazil; 2 Department of Internal Medicine, Division of Infectious Disease, University of Kentucky and Lexington Veterans Affairs Medical Center, Lexington, Kentucky 40506; and 3 Department of Pharmacology, School of Medicine, Missouri University and Truman Memorial Veterans Affairs Hospital, Columbia, Missouri 65212
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Guanylin and uroguanylin compose a family of
natriuretic, diuretic, and kaliuretic peptides that bind to and
activate apical membrane receptor guanylyl cyclase signaling molecules
in renal and intestinal epithelia. Recently, a complementary DNA
encoding an additional member of the guanylin family of cGMP-regulating peptides was isolated from lymphoid tissues of the opossum and was
termed lymphoguanylin (LGN). A peptide analog of opossum LGN was
synthesized containing a single disulfide bond with the internal cysteine-7 replaced by a serine residue
(LGNCys7Ser7). The biological activity of
LGNSer was tested by using a cGMP bioassay with cultured
T84 (human intestinal) cells and opossum kidney (OK) cells.
LGNSer has potencies and efficacies for activation of cGMP
production in the intestinal and kidney cell lines that are 100- and
1,000-fold higher than LGN, respectively. In the isolated perfused rat
kidney, LGNSer stimulated a maximal increase in fractional
Na+ excretion from 24.8 ± 3.0 to 36.3 ± 3.3%
60 min after administration and enhanced urine flow from 0.15 ± 0.01 to 0.24 ± 0.01 ml · g
1 · min
1.
LGNSer (0.69 µM) also increased fractional K+
excretion from 27.3 ± 2.3 to 38.0 ± 3.0% and fractional
Cl
excretion from 26.1 ± 0.8 to 43.5 ± 1.9. A
ninefold increase in the urinary excretion of cGMP from 1.00 ± 0.04 to 9.28 ± 1.14 pmol/ml was elicited by LGNSer,
whereas cAMP levels were not changed on peptide administration. These
findings demonstrate that LGNSer, which contains a single
disulfide bond like native LGN, activates guanylyl cyclase-C (GC-C)
receptors in T84 and OK cells and may be very helpful in studying the
physiological importance of activation of GC-C in vivo.
LGNSer also exhibits full activity in the isolated perfused
kidney equivalent to that observed previously with opossum uroguanylin,
suggesting a physiological role for LGN in renal function. Thus the
single amino acid substitution enhances the activity and potency of LGN.
uroguanylin; guanylin; Escherichia coli heat-stable enterotoxin; guanylyl cyclase-C; kidney; cyclic guanosine 5'-monophosphate
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
GUANYLIN AND UROGUANYLIN ARE small cysteine-rich peptides that were initially isolated from rat jejunum and opossum urine, respectively (5, 20). Both of these peptides share strong structural similarity with heat-stable toxin (STa) peptides secreted by the enterotoxigenic strains of Escherichia coli that cause secretory diarrhea in humans and other animals (12). Guanylin and uroguanylin are produced at high levels in the intestinal mucosa, where they are secreted into the intestinal lumen and into the circulation. However, these peptides have been found in other tissues, including kidney, adrenal medulla, lymphoid tissues, myocardium, brain, and the airway epithelium (6, 8, 12, 38). These peptides bind to and activate apical membrane guanylyl cyclases (GCs) that are expressed in the intestine, kidney, and other epithelia (9). Guanylin and uroguanylin markedly stimulate intestinal chloride and bicarbonate secretion in the intestine via activation of cGMP accumulation in target cells located throughout the intestinal tract (19, 22). Guanylin, uroguanylin, and STa also increase urinary sodium, chloride, potassium, and water excretion in vivo in mice and in the ex vivo perfused rat kidney (2, 11, 18, 29).
Identification of both membrane receptor GCs and a cGMP signaling pathway for STa in the opossum kidney and cultured opossum kidney (OK) cells provided the first evidence for renal mechanisms involving intestinal cGMP-regulating peptides. Fonteles and coworkers (29) then demonstrated that STa induces natriuresis, diuresis, and kaliuresis in the isolated perfused rat kidney. Guanylin and uroguanylin were shown to possess similar natriuretic, diuretic, and kaliuretic activities compared with STa in intestinal and specific renal model systems (2, 11, 25, 29). Guanylin and/or uroguanylin may act physiologically as "intestinal natriuretic hormones" in an endocrine axis linking the intestine to the kidney (15, 18). Such an intestine-kidney signaling mechanism may contribute to a rapid and sustained increase in the urinary excretion of NaCl after a high-salt meal (1, 11, 15, 27).
Recently, a third member of the endogenous guanylin peptide family of
cGMP-regulating hormones was identified by molecular cloning of cDNAs
encoding the polypeptide precursor preprolymphoguanylin (13). Lymphoguanylin (LGN) is widely expressed in many
lymphoid tissues of opossums, but the mRNA for this peptide is most
abundant in the kidney and heart. This finding suggests that LGN may
participate in a paracrine or autocrine intrarenal cGMP signaling
mechanism that could influence Na+ and Cl
transport within the kidney (13). Like guanylin and
uroguanylin, the bioactive form of LGN is found as a 15-residue peptide
located at the COOH terminus of a larger precursor molecule (5,
13, 20). The amino acid sequence of LGN shares 80% identity
with opossum uroguanylin but only 40% identity with guanylin. However, LGN has unique structural features that make it a distinct member of
this family of peptides. Native LGN has three cysteine residues, and
thus only one intramolecular disulfide bond can be formed in this
peptide. In contrast, all of the guanylin and uroguanylin peptides
identified thus far contain two intramolecular disulfide bonds, which
were previously thought to be required for full biological activity of
these peptides (Fig. 1). In a previous
study, synthetic LGN was prepared containing three cysteine residues as
derived from the cDNA structure of preprolymphoguanylin
(13). This peptide was considerably less potent and less
efficacious than either uroguanylin or guanylin when tested in either
OK or T84 intestinal cell cGMP accumulation bioassays. Thus we prepared
an analog of LGN containing only two cysteines, which facilitated the
formation of a single disulfide bond and proper folding of this peptide (Fig. 1). We hypothesized that this analog,
LGNCys7
Ser7, would increase intracellular cGMP
in T84 and OK epithelial cells and cause a significant natriuretic
response in the isolated perfused rat kidney. In the present study, we
demonstrate that LGNCys7
Ser7 has full potency and
efficacy in the stimulation of cGMP accumulation in both T84 and OK
cells compared with the pharmacological properties of uroguanylin. In
the isolated perfused rat kidney, LGNSer markedly increases
the urinary excretion of Na+, K+,
Cl
, and cGMP equivalent to the renal responses that were
previously reported for uroguanylin and STa in this organ system
(11).
|
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Synthesis of LGNSer.
A modified form of opossum LGN (LGNCys7Ser7;
QEECELSINMACTGY) and native opossum uroguanylin were synthesized by
solid-phase synthesis and purified by C18 reverse-phase
HPLC as described in detail elsewhere (1, 5, 20).
Perfused rat kidney protocol.
Adult Wistar-Kyoto rats of either sex, weighing 250-300 g, were
anesthetized with pentobarbital sodium (50 mg/kg body wt ip). Before
each experiment, the animals were fasted for 24 h with free water
ad libitum. The perfusate solution consisted of a modified Krebs-Henseleit solution (MKHS) with the following composition (in mM):
147 Na+, 5 K+, 2.5 Ca2+, 2.0 Mg2+, 110 Cl, 25 HCO3
, 1 SO42
, and 1 PO43
. Six grams of
bovine serum albumin were added to 100 ml of MKHS after a previous
dialysis for 48 h at 4-6°C against a volume 10 times
larger. Immediately before the beginning of each perfusion protocol,
100 mg of glucose, 50 mg of urea, and 50 mg of inulin (Sigma, St.
Louis, MO) were added to the MKHS in a final volume of 100 ml. The pH
was then adjusted to 7.4, and the solution was placed in the perfusion line.
Biochemical analyses.
The perfusate and urine aliquots (50 µl) obtained were analyzed for
Na+ and K+ by flame photometry, and
Cl was determined by spectrophotometry. Inulin was
determined according to the method described by Wasler and coworkers
(37) as modified by Fonteles et al. (10, 11).
Osmolality was determined by freezing-point depression (Needham
Heights, MA).
Urinary cGMP and cAMP measurements.
Immediately after each experiment, the tubes containing urine samples
were reweighed for determination of urine volume. cGMP and cAMP levels
in urine were determined by a cGMP enzymeimmunoassay (EIA; Amersham
Pharmacia Biotech, Piscataway, NJ) or a cAMP EIA (Amersham Pharmacia
Biotech), respectively. Briefly, an aliquot from the urine samples was
diluted 1:10 with a sodium acetate assay buffer in a final volume of
150 µl, followed by acetylation with
-amino-N/tetrethylammonium (1:2, vol/vol). Then, 100 µl of cGMP- or cAMP-rabbit antiserum were added to each well of a microtiter plate coated with anti-rabbit IgG antibody. Fifty
microliters of each acetylated urine sample were then added to each
well, and the plate was incubated for 2 h at 4°C. The cGMP- or
cAMP-peroxidase conjugate (100 µl) was then placed in each well, and
the plate was incubated at 4°C for 1 h. Each well was washed
four times with PBS with 0.05% Tween 20, and 200 µl of
1,1'-trimethylene-bis(4-formylpyridinium bromide) dioxime
substrate were placed into each well and incubated for 30 min at
25°C. Then, 100 µl of a 1 M sulfuric acid solution were added to
each well. After 10 min at RT, the absorbance at 450 nm was measured by
spectrophotometry (model 2550, EIA Reader, Bio-Rad Laboratories). The
cGMP and cAMP concentrations of each urine sample were determined in
duplicate or triplicate by comparison with known standards.
Cell culture.
T84 cells were cultured in DMEM/Ham's F-12 medium (1:1) supplemented
with 5% fetal bovine serum, 60 mg of penicillin, and 100 mg of
streptomycin/ml as described in detail elsewhere (3, 5, 13,
20). OK (OK-) cells were cultured in DMEM and Ham's F-12
medium (1:1) supplemented with 5% fetal bovine serum as previously described (13, 16).
cGMP accumulation bioassay. T84 and OK cells were cultured in 24-well plastic dishes, and cGMP levels were measured in control and agonist-stimulated cells by RIA (1, 5, 13, 20). Synthetic peptides were diluted in 200 µl DMEM containing 20 mM HEPES and 1 mM of IBMX at pH 7.4. Cells were washed with DMEM before addition of 200 µl DMEM containing either agonist peptides or vehicle to T84 or OK cells, followed by incubation at 37°C for 40 min. After incubation, the medium was aspirated, the cells were washed with PBS, and 0.2 ml of 3.3% perchloric acid was added to each well to extract cGMP. The cell extract was neutralized and used for measurement of cGMP by RIA as previously described (5, 20). cAMP levels were not measured from these cellular extracts because neither uroguanylin nor STa increases this cyclic nucleotide in these cells (1, 5, 16).
Data analyses. For the experiments with perfused kidneys, the data (means ± SE) were averaged in triplicate between 30-min intervals. Statistical analyses were carried out by one-way ANOVA and by Student's t-test when applicable. There were at least four to five perfused-kidney experiments for each data point.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The synthetic LGNSer peptide containing a single
disulfide bond was tested for biological activity by using both OK and
T84 cell cGMP accumulation bioassays (Fig.
2). LGNSer stimulates cGMP
production with apparent potencies and efficacies that are equal to
those observed for opossum uroguanylin in these cGMP bioassays with
kidney and intestinal cell lines. Thus LGNSer appears to be
a full agonist for the receptor GC signaling molecules that are
expressed in these cultured cells (for human T84 cells, GC-C; for OK
cells, OK-GC), even though this peptide contains only one
intramolecular disulfide bond.
|
LGNSer (0.23 µM) induced a significant natriuretic
response in the isolated perfused kidney, reflected as both an increase
in %ENa+ from 24.7 ± 3.0 to 36.3 ± 3.3% at 90 min (P 0.05; Fig.
3) and a decrease in
%RNa+ (Table 1).
A prominent and sustained diuresis was also observed at this concentration of LGNSer, with urine flow increasing from
0.15 ± 0.01 to 0.24 ± 0.01 ml · g
1 · min
1
(P < 0.05; Fig. 4). The
changes in %EK+ and
%RK+ elicited by 0.23 µM LGNSer
were not statistically significant (Tables 1 and
2). At this concentration of LGN, no
changes occurred in either %ECl
or
%RCl
(Tables 1 and 2). The urinary excretion of cGMP increased significantly (from 1.02 ± 0.04 to 8.84 ± 0.82 pmol/ml, P
0.05) at 60 min after treatment with
LGNSer (Fig. 5, 90-min time
point). The increase in urinary cGMP excretion paralleled the increase
in Na+ excretion and urine flow. No significant changes
were observed in either GFR or perfusion pressure (Table 2). In
addition, urinary cAMP levels in the rat kidneys treated with
LGNSer did not vary from those in the control
kidneys. Also, by the end of the experiment, the cAMP levels were
virtually undetectable in both the control and
LGNSer-treated rat kidneys.
|
|
|
|
|
At the higher concentration of LGNSer (0.69 µM), we found
a significant increase in the %RNa+ (Fig. 3)
and a corresponding decrease in %RNa+ from
77.1 ± 1.0 to 64.0 ± 0.7% by 90 min (P 0.05; Table 1). LGNSer also induced a diuresis, with urine
flow increasing from 0.19 ± 0.02 to 0.33 ± 0.02 ml · g
1 · min
1 by 120 min
(P
0.05) (Fig. 4). At this concentration of
LGNSer, we also observed a significant kaliuresis, with an
increase in %EK+ (Table 2) and a decrease in
%RK+ from 72.6 ± 2.3 to 62.0 ± 2.9% (P
0.05). A significant increase in
%ECl
from 26.1 ± 0.8 to 37.9 ± 1.9% (P
0.05) and a decrease in
%RCl
were also observed (Tables 1 and 2). An
increase in perfusion pressure with a higher LGNSer
concentration was observed (Table 2).
LGNSer elicited striking increases in the urinary excretion
of cGMP at 0.69 µM, with cGMP increasing from the control level of 1.00 ± 0.04 to 9.28 ± 1.14 pmol cGMP/ml by 90 min after
peptide administration (P 0.05) (Fig. 5). There were
no significant changes in GFR (Table 2), osmolar clearance (data not
shown), and cAMP (Fig. 5) at the concentrations of LGNSer
that were tested in these experiments. Thus LGNSer elicits
marked increases in urinary cGMP excretion in association with
substantial increases in the excretion of Na+,
K+, and water, probably through activation of receptor GC
signaling molecules located on the surface of target cells in the renal tubules.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A synthetic form of LGN containing two cysteine residues and a single disulfide bond has been prepared (LGNSer) and found to be equipotent compared with native opossum uroguanylin in both the OK and T84 cell cGMP bioassays. In marked contrast, we previously found that synthetic LGN prepared with three cysteine residues in its native form had markedly reduced potency compared with guanylin or uroguanylin in these bioassays (12). This finding is consistent with the hypothesis that a fully active guanylin-like peptide that contains only one intramolecular disulfide bond can activate the cognate guanylin receptors of kidney and intestine. Therefore, the secondary structure and three-dimensional conformation of this LGN analog must be similar to those previously elucidated for guanylin and uroguanylin containing two disulfide bonds (12). The advantages of preparing a guanylin peptide with a single disulfide bond are that simple air-oxidation steps can be used to elicit folding of this peptide into an active conformation. In contrast, we previously used a more complex method of directed disulfide bond formation to ensure that the intramolecular disulfides that are formed in the guanylin peptides are those connecting the first to third and second to fourth cysteine residues in the linear peptide chain (Fig. 1) (5, 20). If directed folding in a stepwise manner is not used for the guanylin and uroguanylin peptides, little biologically active peptide is formed because the subsequent disulfide bond formation results in an inactive disulfide isomer of the guanylin peptides (24). The synthesis of LGNSer containing a single disulfide bond will facilitate the preparation of a fully active guanylin-family peptide to further investigate the physiological roles of this novel class of cGMP-regulating peptides.
The present study characterizes the renal effects of a new member of the guanylin peptide family. LGNSer has natriuretic, diuretic, and kaliuretic activities in the isolated perfused rat kidney. The renal effects of LGNSer are surprisingly quite similar to those previously described for uroguanylin (11). At the concentrations of uroguanylin and LGNSer that have been tested, both peptides elicit prominent natriuretic responses in the isolated perfused kidney (11). It has also been demonstrated that E. coli STa, the molecular mimic of guanylin and uroguanylin, has natriuretic, diuretic, and kaliuretic activities in the isolated perfused rat kidney (29).
Receptors for guanylin/uroguanylin/STa have been shown to be localized to both medullary and cortical segments in the rat nephron after 125I-labeled guanylin was intravenously injected (17). Also, autoradiography employing 125I-labeled STa to opossum kidney tissue sections demonstrated binding sites for STa receptors (16, 25). Carrithers et al. (3) report the presence of GC-C receptors along distinct regions of the rat nephron. This suggests that receptors for the guanylin family of peptides may exist on cells located in different segments of the nephron, thus influencing tubular function (12). In the opossum, the guanylin/uroguanylin/LGN/STa receptor is known as OK-GC, which is the renal isoform of mammalian intestinal GC-C found in mice, rats, and humans (26, 30). OK-GC is present in OK cells, and GC-C is present in T84 cells (14, 25). On ligand binding in intestinal or kidney epithelial cells, these receptors increase the intracellular content of cGMP. We have demonstrated in this study that LGNSer stimulates cGMP accumulation in both the OK and T84 cells with potencies and efficacies that are comparable to that of native opossum uroguanylin. Furthermore, LGNSer is over 100 times more potent than native LGN in T84 cells and OK cells, respectively (13). These results suggest that LGNSer can activate either OK-GC or GC-C.
The fact that urinary cGMP excretion is increased ninefold 60 min after
LGNSer administration in the isolated perfused rat kidney
suggests that this cyclic nucleotide may mediate the natriuretic
effects of LGN. Furthermore, the natriuresis and the urinary cGMP
accumulation are consistent with the hormone effect in the kidney
preparation. On the other hand, cAMP levels do not increase in the
urine fractions (Fig. 5). The basal levels observed in the control and
treatment periods are likely to be remnants of vascular cAMP in this
system. Additional studies have supported the fact that
8-bromoadenosine 3',5'-cyclic monophosphate causes natriuresis
(29). These effects were also observed with STa, which is
the bacterial mimic peptide of the endogenous family of guanylin
peptides. Thus the increases in urinary Na+,
K+, and Cl on LGNSer treatment
are consistent with a cGMP-dependent mechanism.
In the intestine, it has been shown that STa and guanylin specifically
signal through cGMP-dependent protein kinase II (cGK-II; 33-36),
causing Cl secretion from native epithelial cells.
However, guanylin/uroguanylin/LGN target cells may also increase
transepithelial Cl
and HCO3
secretion
by interacting with and stimulating the enzymatic activities of
cAMP-dependent protein kinase A-II (PKA-II; 12, 15). Disabling the gene
encoding cGK-II results in a loss of fluid secretion responses to STa
and guanylin in vivo and a marked decrease in anion secretion in vitro
(33). Short-circuit current responses to
STa/guanylin in vitro were partly retained in the intestine of
cGK-II(
/
) mice, indicating that alternative pathways exist for cGMP
regulation by the guanylin peptides. It was previously shown in T84
cells that STa/guanylin-induced cGMP activates Cl
secretion by cross-activation of PKA-II rather than by activation of
cGK-II (12, 15). A third cGMP signaling mechanism may be through cGMP binding to specific sites on cGMP-dependent
phosphodiesterases, leading to decreased cAMP hydrolysis. Thus high
levels of cGMP would indirectly increase intracellular cAMP, which, in
turn, activates PKA-II (7). The renal mechanism(s) for the
family of guanylin-like peptides is unknown and has not been
investigated. Also, there is no evidence to demonstrate that LGN
signals through cGK-II in the kidney. Presently, we are testing
specific inhibitors to the cGK-II and PKA pathways to determine the
downstream signaling pathway(s) for guanylin-like peptide (and LGN)
action in the kidney.
Because LGN was identified in a metatherian (marsupial) mammal (Didelphis virginiana), it is possible that that the LGN gene could have arisen by gene duplication after the evolutionary divergence of eutherian (placental) and metatherian mammals occurred (23). An ancestral uroguanylin-like gene could be the evolutionary precursor for both uroguanylin and LGN genes of the opossum. Because a homolog of LGN has not yet been identified in representative eutherian mammals, a physiological role in the body for LGN can only be postulated for the opossum at the present time (13).
In conclusion, an analog of LGN containing a single disulfide bond increased cGMP in OK and T84 (human intestinal) cells. This analog, LGNSer, is more potent than native LGN and equipotent to uroguanylin in both of these in vitro cell models. Treatment of the ex vivo perfused kidneys of rats with LGNSer resulted in substantial increases in the urinary excretion of Na+, K+, water, and cGMP. In the opossum, LGN may participate in an intrarenal paracrine signaling pathway that influences kidney function via the second-messenger cGMP and influence sodium transport in the kidney. Furthermore, LGNSer, which is more easily synthesized than LGN, uroguanylin, or guanylin, can be employed to elucidate the renal mechanisms as well as the specific nephron sites of action for the guanylin family of peptides.
![]() |
ACKNOWLEDGEMENTS |
---|
We gratefully acknowledge Jose Amadeus for animal care, Silvia F. Franca for expert technical assistance, and Domingos Barreto for biochemical determinations.
![]() |
FOOTNOTES |
---|
The present research was supported by a grant form the Conselho Nacional de Pesquisas, Brazil (to M. C. Fonteles). L. R. Forte, R. N. Greenberg, and S. L. Carrithers were supported by the Medical Research Service, Department of Veterans Affairs, Washington, DC.
Part of this work was published as an abstract for Experimental Biology '99, Washington, DC, April 27-21, 1999.
Address for reprint requests and other correspondence: M. C. Fonteles, Clinical Research Unit, CP 3229 UPC-UFC/UECe, 60434 Fortaleza, Ceara, Brazil (E-mail: reitor{at}uece.br).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 13 March 2000; accepted in final form 11 September 2000.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Carrithers, SL,
Eber S,
Forte LR,
and
Greenberg RN.
Increased urinary excretion of uroguanylin in patients with congestive heart failure.
Am J Physiol Heart Circ Physiol
278:
H538-H547,
2000
2.
Carrithers, SL,
Hill MJ,
Johnson BR,
O'Hara SM,
Jackson BA,
Ott CE,
Lorenz J,
Mann EA,
Giannella RA,
Forte LR,
and
Greenberg RN.
Renal effects of guanylin and uroguanylin in vivo.
Braz J Med Biol Res
32:
1337-1344,
1999[ISI][Medline].
3.
Carrithers, SL,
Taylor B,
Cai WY,
Johnson BR,
Ott CE,
Greenberg RN,
and
Jackson BA.
Guanylyl cyclase-C receptor mRNA distribution along the rat nephron.
Regul Pept
24:
65-74,
2000.
4.
Coulsor, R.
Metabolism and excretion of exogenous adenosine-3',5'-monophosphate and guanosine-3',5'-monophosphate. Studies in the isolated perfused rat kidney and in the intact rat.
J Biol Chem
251:
4958-4967,
1976[Abstract].
5.
Currie, MG,
Fok KF,
Kato J,
Moore RJ,
Hamra FK,
Duffin KL,
and
Smith CE.
Guanylin: an endogenous activator of intestinal guanylate cyclase.
Proc Natl Acad Sci USA
88:
947-951,
1992.
6.
De Sauvage, FJ,
Keshav S,
Kuang WJ,
Gillet N,
Henzel W,
and
Goeddel DV.
Precursor structure, expression and tissue distribution of human guanylin.
Proc Natl Acad Sci USA
89:
9089-9093,
1992[Abstract].
7.
Dousa, TP.
Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney.
Kidney Int
55:
29-62,
1999[ISI][Medline].
8.
Fan, X,
Hamra FK,
Freeman RH,
Eber SL,
Krause WJ,
Lim RW,
Pace VM,
Currie MG,
and
Forte LR.
Uroguanylin: cloning of preprouroguanylin cDNA, mRNA expression in the intestine and heart and isolation of uroguanylin and prouroguanylin from plasma.
Biochem Biophys Res Commun
219:
457-462,
1996[ISI][Medline].
9.
Fan, X,
Wang Y,
London RM,
Eber SL,
Krause WJ,
Freeman RH,
and
Forte LR.
Signaling pathways for guanylin and uroguanylin in the digestive, renal, central nervous, reproductive and lymphoid systems.
Endocrinology
138:
4636-4648,
1997
10.
Fonteles, MC,
Cohen JJ,
Black AJ,
and
Wertheim SJ.
Support of kidney function by long-chain fatty acids derived from renal tissue.
Am J Physiol Renal Fluid Electrolyte Physiol
244:
F235-F246,
1983[ISI][Medline].
11.
Fonteles, MC,
Greenberg RN,
Monteiro HSA,
Currie MG,
and
Forte LR.
Natriuretic and kaliuretic activities of guanylin and uroguanylin in the isolated perfused rat kidney.
Am J Physiol Renal Physiol
275:
F191-F197,
1998
12.
Forte, LR.
Guanylin regulatory peptides: structures, biological activities mediated by cyclic GMP and pathobiology.
Regul Pept
81:
25-39,
1999[ISI][Medline].
13.
Forte, LR,
Eber SL,
Fan X,
London RM,
Wang Y,
Rowland LM,
Chin DT,
Freeman RH,
and
Krause WJ.
Lymphoguanylin: cloning and characterization of a unique member of the guanylin peptide family.
Endocrinology
140:
1800-1806,
1999
14.
Forte, LR,
Eber SL,
Turner JT,
Freeman RH,
Fok KF,
and
Currie MG.
Guanylin stimulation of Cl secretion in human intestinal T84 cells via cyclic guanosine monophosphate.
J Clin Invest
91:
2423-2428,
1993[ISI][Medline].
15.
Forte, LR,
Fan X,
and
Hamra FK.
Salt and water homeostasis: uroguanylin is a circulating peptide hormone with natriuretic activity.
Am J Kidney Dis
28:
296-304,
1996[ISI][Medline].
16.
Forte, LR,
Krause WJ,
and
Freeman RH.
Receptors and cGMP signaling mechanism for E. coli enterotoxin in opossum kidney.
Am J Physiol Renal Fluid Electrolyte Physiol
255:
F1040-F1046,
1988
17.
Furuya, S,
Naruse S,
Ando E,
Nokihara K,
and
Hayakawa T.
Effects and distribution of intravenously injected 125I-guanylin in rat kidney examined by high-resolution light microscopic radioautography.
Anat Embryol (Berl)
196:
185-193,
1997[ISI][Medline].
18.
Greenberg, RN,
Hill M,
Craytzer J,
Krause WJ,
Eber SL,
Hamra FK,
and
Forte LR.
Comparison of effects of uroguanylin, guanylin, Eschericha coli heat-stable STa in mouse intestine and kidney: evidence that uroguanylin is an intestinal natriuretic hormone.
J Invest Med
45:
276-282,
1997[ISI][Medline].
19.
Guba, M,
Kuhn M,
Forssmann WG,
Classen M,
Gregor M,
and
Seidler U.
Guanylin strongly stimulates rat duodenal HCO3 secretion: proposed mechanisms and comparison with other secretagogues.
Gastroenterology
111:
1558-1568,
1996[ISI][Medline].
20.
Hamra, FK,
Forte LR,
Eber SL,
Pidhorodjeckyj NV,
Krause WJ,
Freeman RH,
Chin DT,
Tompkins JA, K,
Fok F,
Smith CE,
Smith KL,
Siegel NR,
and
Currie MG.
Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase.
Proc Natl Acad Sci USA
90:
10464-10468,
1993[Abstract].
21.
Heuze-Joubert, I,
Mennecier P,
Simonet S,
Laubie M,
and
Verbeuren TJ.
Effect of vasodilators, including nitric oxide, on the release of cGMP and cAMP in the isolated perfused rat kidney.
Eur J Pharmacol
220:
161-171,
1992[ISI][Medline].
22.
Ieda, H,
Naruse S,
Kintagawa M,
Ishiguro H,
and
Hayakawa T.
Effects of guanylin and uroguanylin on rat jejunal fluid and electrolyte transport: comparison with heat-stable enterotoxin.
Regul Pept
79:
165-171,
1999[ISI][Medline].
23.
Janke, A,
Xu X,
and
Amarson U.
The complete mitochondrial genome of walaroo (Macropus robustus) and the phylogenetic relationship among Monotremata, Marsupiala, and Eutheria.
Proc Natl Acad Sci USA
94:
1276-1281,
1997
24.
Klodt, J,
Kuhn M,
Marx UC,
Martin S,
Rosch P,
Forsmmann WG,
and
Andermann K.
Synthesis, biological activity, and isomerism of guanylate-cyclase C-activating peptides guanylin and uroguanylin.
J Pept Res
50:
222-230,
1997[ISI][Medline].
25.
Krause, WJ,
Freeman RH,
and
Forte LR.
Autoradiographic demonstration of specific binding sites for E. coli enterotoxin in various epithelia of the North American opossum.
Cell Tissue Res
260:
387-394,
1990[ISI][Medline].
26.
Krause, WJ,
London RM,
Freeman RH,
and
Forte LR.
The guanylin and uroguanylin peptide hormones and their receptors.
Acta Anat
160:
213-231,
1997[ISI][Medline].
27.
Lennane, RJ,
Peart WS,
Carey RM,
and
Shaw J.
Comparison of natriuresis after oral and intravenous sodium loading in sodium-depleted rabbits: evidence for a gastrointestinal or portal monitor of sodium intake.
Clin Sci Mol Med
49:
433-436,
1975[ISI][Medline].
28.
Li, Z,
Perkins AG,
Peters MF,
Campa MJ,
and
Goy MF.
Purification, cDNA sequence and tissue distribution of rat uroguanylin.
Regul Pept
68:
45-56,
1997[ISI][Medline].
29.
Lima, AA,
Monteiro HSA,
and
Fonteles MC.
The effects of Eschericha coli heat-stable enterotoxin in renal sodium tubular transport.
Pharmacol Toxicol
70:
163-167,
1992[ISI][Medline].
30.
London, RM,
Eber SL,
Visweswariah SS,
Krause WJ,
and
Forte LR.
Structure and activity of OK-GC: a kidney receptor activated by guanylin peptides.
Am J Physiol Renal Physiol
276:
F882-F891,
1999
31.
Martinez-Maldonato, M,
and
Opava-Stitzer S.
Free water clearance during saline, manitol, glucose and urea diuresis in rats.
J Physiol (Lond)
280:
487-497,
1978[ISI][Medline].
32.
Miyazato, M,
Nakazato M,
Matsukara S,
Kangawa K,
and
Matsuo H.
Uroguanylin gene expression in the alimentary tract and extra-intestinal tissues.
FEBS Lett
398:
170-174,
1996[ISI][Medline].
33.
Pfeifer, A,
Aszodi A,
Seidler U,
Ruth P,
Hoffman F,
and
Fassler R.
Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II.
Science
274:
2082-2086,
1996
34.
Vaandrager, AB,
Bot AGM,
and
DeJonge HR.
Guanosine 3',5'-cyclic monophosphate-dependent protein kinase II mediates heat-stable enterotoxin-provoked chloride secretion in rat intestine.
Gastroenterology
112:
437-443,
1997[ISI][Medline].
35.
Vaandrager, AB,
Edixhoven M,
Bot AGM,
Kroos MA,
Jarchau T,
Lohmann S,
Genieser HG,
and
DeJonge HR.
Endogenous type II cGMP-dependent protein kinase exists as a dimer in membranes and can be functionally distinguished from the type I isoforms.
J Biol Chem
272:
11816-11823,
1997
36.
Vaandrager, AB,
Smolenski A,
Tilly BC,
Houtsmuller AB,
Ehlert EME,
Bot AGM,
Edixhoven M,
Boomaars WEM,
Lohmann SM,
and
DeJonge HR.
Membrane targeting of cGMP-dependent protein kinase is required for cystic fibrosis transmembrane conductance regulator Cl channel activation.
Proc Natl Acad Sci USA
95:
1466-1471,
1998
37.
Wasler, M,
Davidosn DG,
and
Orloff J.
The renal clearance of alkali-stable inulin.
J Clin Invest
34:
1520-1523,
1955[ISI].
38.
Whitaker, TL,
Witte DP,
Scott MC,
and
Cohen MB.
Uroguanylin and guanylin: distinct but ovelapping patterns of messenger RNA expression in mouse intestine.
Gastroenterology
113:
1000-1006,
1997[ISI][Medline].
39.
Wiegand, RC,
Kato J,
Huang MD,
Fok KF,
Kachur JF,
and
Currie MG.
Human guanylin: cDNA isolation, structure and activity.
FEBS Lett
311:
150-154,
1992[ISI][Medline].
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Visit Other APS Journals Online |