1 Forschungsinstitut für Molekulare Pharmakologie, Campus Berlin-Buch,
Robert-Rössle-Strasse 10, 13125 Berlin, Germany
2 Universita de Bari, Dipartimento di Fisiologia Generale e Ambientale, Via
Amendola 165/A, 70126 Bari, Italy
3 Freie Universität Berlin, Institut für Pharmakologie, Thielallee
67-73, 14195 Berlin, Germany
* Author for correspondence (e-mail: klussmann{at}fmp-berlin.de)
Accepted 23 April 2003
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Summary |
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Key words: PGE2, Aquaporin, AQP2, Rho, Vasopressin, Kidney
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Introduction |
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Prostaglandins (PGs) act as autocrine and paracrine lipid mediators,
controlling many physiological processes
(Funk, 2001;
Breyer and Breyer, 2000
). The
effects of prostaglandin E2 (PGE2) on the osmotic water
permeability of the collecting duct have been investigated by using various
animal models. In the absence of AVP, basolaterally or luminally administered
PGE2 increases basal osmotic water permeability in rabbit cortical
collecting ducts, most likely by stimulation of cAMP synthesis via
Gs/adenylyl cylase (Sakairi et
al., 1995
). In contrast, in AVP-stimulated rabbit cortical
collecting ducts, basolaterally administered PGE2 inhibits osmotic
water permeability. The effect has been ascribed to inhibition of cAMP
synthesis via Gi/adenylyl cyclase (Sonnenburg et al., 1988). In
addition, PGE2 induces elevation of cytosolic Ca2+ in
rabbit collecting ducts by stimulating both a release from intracellular
stores and influx from the extracellular medium. Elevation of cytosolic
Ca2+, via the G protein Gq, has also been suggested to
contribute to the diuretic effect of PGE2
(Hebert et al., 1990
;
Hebert et al., 1993
;
Hebert, 1994
). In the rat
terminal inner medullary collecting duct, PGE2 alone has no effect
on basal osmotic water permeability, but attenuates AVP-induced increases in
osmotic water permeability. Again, this was suggested to be due to elevation
of cytosolic Ca2+ (Nadler et
al., 1992
).
PGE2 interacts with four different G protein-coupled receptors
designated EP1, EP2, EP3 and EP4
(Coleman et al., 1994;
Narumiya et al., 1999
;
Breyer and Breyer, 2001
;
Namba et al., 1993
;
Hatae et al., 2002
). The EP
receptor subtypes expressed by principal cells have not been identified, but
the inhibitory effect of PGE2 on the AVP-induced increase in
osmotic water permeability is likely to be mediated by EP1 and/or
EP3 receptors, which are coupled to the Gq/phospholipase
C (PLC) and Gi/adenylyl cyclase system, respectively
(Sakairi et al., 1995
). This
assumption is supported by the finding that the stable PGE2
analogue, sulprostone, a selective EP1/EP3 receptor
agonist, inhibits the AVP-induced increases in osmotic water permeability in
the rabbit cortical collecting duct
(Hebert et al., 1993
;
Hebert, 1994
). However, the
underlying signal transduction pathways are not understood. EP3
receptors, in addition to coupling to the Gi/adenylyl cyclase
system, mediate Rho activation, most likely through the G proteins
G12/13, and subsequently the formation of stress fibers
(Negishi et al., 1995
;
Hasegawa et al., 1997
;
Aoki et al., 1999
). Activated
Rho poses a block to the AVP-induced AQP2 shuttle in principal cells
(Klussmann et al., 2001b
;
Tamma et al., 2001
). Thus, we
hypothesized that PGE2 exerts its diuretic effect through
activation of Rho via EP3 receptors (see above). To
investigate this possibility, the effects of sulprostone, combined with an
EP1 receptor antagonist, SC19220, on the cellular localization of
AQP2, on Rho activity and on F-actin were analyzed using primary cultured rat
inner medullary collecting duct (IMCD) cells. In addition, levels of cytosolic
Ca2+ and adenylyl cyclase activity were determined. Our data
suggest that activation of the G12/13/Rho pathway rather than
inhibition of adenylyl cyclase or stimulation of PLC (increase in cytosolic
Ca2+) underlies the EP3 receptor-mediated diuretic
action of PGE2 observed in the presence of AVP. In addition, they
provide strong evidence for a central role of Rho in both diuretic and
antidiuretic responses.
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Materials and Methods |
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Culture of IMCD cells, immunofluorescence microscopy and
quantification of immunofluorescence intensities
IMCD cells were obtained from rat renal inner medullae and cultured on
cover slips as described previously (Maric
et al., 1998). Bt2cAMP was added to the culture medium
for maintenance of AQP2 expression. Bt2cAMP was removed 16 hours
prior to experiments, which were performed 6 days after seeding. AQP2 was
detected by confocal laser scanning microscopy (LSM 410; Carl Zeiss, Jena,
Germany) using specific antibodies raised against the C terminus of AQP2 and
Cy3-conjugated anti-rabbit secondary antibodies
(Klussmann et al., 1999
;
Klussmann et al., 2001b
;
Maric et al., 1998
). F-actin
was detected after staining with tetramethyl-rhodamine isothiocyanate
(TRITC)-conjugated phalloidin by confocal laser scanning microscopy [LSM 410
(Klussmann et al.,
2001b
)].
For quantification of the effects of AVP, forskolin, Bt2cAMP,
sulprostone and SC19220 on AQP2 localization, the ratio of
intracellular/plasma membrane fluorescence intensities was calculated as
described previously (Klussmann et al.,
1999; Klussmann et al.,
2001b
). For all groups, mean and standard error values were
calculated. Statistical analyses were performed using the Student's
t-test and one-way analysis of variance
(Klussmann et al., 1999
;
Klussmann et al., 2001b
).
Rho pull-down assay and western blotting
The pull-down of active GTP-bound Rho from IMCD cells was essentially
carried out as described previously (Ren
and Schwartz, 2000). In brief, IMCD cells were grown in 60 mm
dishes and incubated with agonists as indicated. GTP-Rho was precipitated from
lysates derived from 7 confluent dishes of IMCD cells using the GST-Rhotekin
fusion protein (20-30 µg) coupled to glutathion Sepharose 4B. GTP-Rho was
eluted by boiling the precipitate in Laemmli buffer (10 minutes) containing
DTT (40 mM). Total RhoA in IMCD cell lysates and precipitated GTP-RhoA were
detected by western blot analysis using commercially available anti-RhoA
monoclonal antibodies (Santa Cruz Biotechnology, Heidelberg, Germany) and
peroxidase-conjugated anti-mouse secondary antibodies. Signals were visualized
using the Lumi-light western blot detection system and a Lumi-Imager F1 (Roche
Diagnostics, Mannheim, Germany). To quantify the amount of active RhoA, signal
densities were determined and related to the signal densities obtained for
total RhoA. Ratios obtained for the various experimental conditions were
normalized to those ratios obtained for control cells. Statistical analysis
was carried out using the Newman-Keuls multiple comparison test.
Adenylyl cyclase assay
Preparation of crude membrane fractions and the adenylyl cyclase assay were
carried out as described previously
(Oksche et al., 1996;
Schülein et al., 1996
).
[32P]cAMP was isolated using the two column method
(Salomon et al., 1974
).
Statistical analysis was carried out using the unpaired t-test for
independent single assay results.
Inositol-1,4,5-trisphosphate (InsP3) assay
IMCD cells were grown in 24-well plates. Five days after seeding, the
culture medium was replaced by Bt2cAMP-free medium containing 74
kBq/ml myo-[2-3H]inositol (specific activity 37 MBq/ml). For the
uptake of myo-[2-3H]inositol, the cells were grown for 20 hours at
37°C. The cells were washed with Bt2cAMP-free culture medium
containing 10 mM LiCl and further incubated in Bt2cAMP-free medium
containing agonists as indicated. Total inositolphosphates were assayed as
described previously (Kirk et al.,
1990). Changes in the content of total inositolphosphates are
largely due to the formation of inositol-1,4,5-trisphosphate
(InsP3) and therefore described as changes in
InsP3 content.
Determination of cytosolic Ca2+
Measurements of cytosolic Ca2+ were essentially performed as
described previously (Schaefer et al.,
2000). In brief, IMCD cells were grown to confluency on glass
coverslips. Fura-2-AM (Molecular Probes, Leiden, The Netherlands) loading was
carried out by incubation of the cells in Hepes-buffered saline (128 mM NaCl,
6 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 5.5 mM glucose, 0.5%
bovine serum albumine, 10 mM Hepes, pH 7.4, 10 µM fura-2-AM; 30 minutes,
37°C). Coverslips were mounted in a custom-made chamber, overlaid with HBS
buffer and placed on an inverted epifluorescence microscope (Axiovert 100,
Carl Zeiss, Jena, Germany) equipped with a monochromator (Polychrome II,
TILL-Photonics, Martinsried, Germany). Agonists were added as indicated.
Thapsigargin was applied at the end of each experiment to prevent the internal
Ca2+ stores limiting the responses to sequentially applied
agonists. Fura-2 was alternatively excited at 340, 358, and 380 nm. Emitted
light was filtered through a 505-nm long-pass filter and recorded with a 12
bit cooled CCD camera (Imago, TILL-Photonics). Cytosolic Ca2+
concentrations were calculated as described
(Grynkiewicz et al., 1985
). In
each imaging experiment, data from 30-80 individual cells were collected.
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Results |
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|
|
Stimulation of EP3 receptors induces the formation of
stress fibers in IMCD cells
EP3 receptor-mediated activation of Rho and subsequent formation
of stress fibers has recently been reported
(Hasegawa et al., 1997). In
IMCD cells, activation of Rho is accompanied by formation of stress fibers and
prevents AQP2 translocation in response to elevation of cAMP
(Klussmann et al., 2001b
).
Therefore, the ability of sulprostone to induce the formation of stress fibers
in IMCD cells was examined. Stress fibers were detected by staining F-actin
with TRITC-conjugated phalloidin and visualization by laser scanning
microscopy (Fig. 3). As
reported, AVP caused a decrease of stress fibers
(Klussmann et al., 2001b
). In
contrast, sulprostone alone or combined with SC19220 induced the formation of
stress fibers under both conditions, i.e. in the presence or absence of AVP.
SC19220 alone did not influence the content of stress fibers in non-stimulated
cells, nor did it inhibit the AVP-induced depolymerization of stress fibers.
The data suggest that stimulation of the V2 and EP3 receptor by AVP
and sulprostone/SC19220, respectively, has opposing effects on the F-actin
cytoskeleton in IMCD cells.
|
Bidirectional control of Rho by antidiuretic and diuretic agents in
IMCD cells
We have previously shown that AVP and C. difficile toxin B induce
a depolymerization of F-actin in IMCD cells
(Klussmann et al., 2001b)
(Fig. 3). Here, we determined
the effects of AVP, toxin B and of sulprostone on RhoA activity
(Fig. 4A,C). Active (GTP-bound)
RhoA was quantitatively analyzed by pull-down assays, using the Rho-binding
domain of Rhotekin fused to GST (Ren and
Schwartz, 2000
). AVP and toxin B caused a decrease in the amount
of active RhoA compared to control cells
(Fig. 4A,C). In contrast,
sulprostone, alone or combined with SC19220, increased RhoA activity
(Fig. 4B,C). AVP, added to
cells preincubated with sulprostone alone, decreased RhoA activity but the
level of RhoA activity observed in cells incubated with AVP alone was not
reached (Fig. 4C). In cells
incubated with sulprostone, SC19220 and AVP, RhoA activity was similar to that
of control cells, indicating that selective EP3 receptor
stimulation abolished the AVP-mediated inhibition of RhoA
(Fig. 4B,C). The data reveal a
bidirectional control of RhoA activity in IMCD cells with the antidiuretic
agent AVP inhibiting and the diuretic agent sulprostone (combined with
SC19220) stimulating it. In addition, the data suggest that in the presence of
AVP the EP3 receptor-induced stimulation of RhoA is attenuated by
EP1 receptor activation (see above; Figs
1 and
2).
|
EP3 receptor stimulation prevents AQP2 translocation
independently of cAMP
Our results indicate that Rho activation is the cellular mechanism
underlying EP3 receptor-mediated diuresis. However, previous
studies suggested that inhibition of the Gi/adenylyl cyclase system
contributes to the diuretic effect of PGE2 (Sonnenburg et al.,
1988; Breyer and Breyer, 2001).
Therefore, the effect of sulprostone on AVP-stimulated adenylyl cyclase
activity was determined in IMCD cell membrane preparations
(Fig. 5). Sulprostone did not
stimulate adenylyl cyclase activity but reduced the AVP-stimulated adenylyl
cyclase activity by about 18%.
|
To test whether EP3 receptor-mediated inhibition of adenylyl
cyclase is relevant for the inhibition of AVP-induced AQP2 translocation, the
effects of sulprostone and SC19220 on the AQP2 shuttle were determined in IMCD
cells exposed to either high levels of dibutyryl cyclic adenosine
monophosphate (Bt2cAMP, 500 µM) or forskolin (100 µM), a
strong, direct activator of adenylyl cyclase.
Fig. 6 shows that even under
these conditions, sulprostone alone or combined with SC19220, maintained its
ability to inhibit the AQP2 shuttle, indicating that the inhibition of the
AQP2 shuttle through EP3 receptors is independent of cellular cAMP
levels. Thus, as in many other systems, the receptor-mediated inhibition of
adenylyl cyclase does apparently not contribute to the cellular response. A
quantitative analysis of the cellular distribution of AQP2 is shown in
Fig. 7 [compare
Fig. 2
(Klussmann et al., 1999;
Klussmann et al., 2001b
)].
|
|
EP3 receptor stimulation neither induces formation of
InsP3 nor elevation of cytosolic Ca2+ in IMCD
cells
Elevation of cytosolic Ca2+ in response to
PGE2/sulprostone stimulation of rabbit cortical collecting ducts
has also been suggested to contribute to the inhibitory effect of
PGE2 on AVP-induced increases in osmotic water permeability
(Hebert, 1994). We, therefore,
investigated the effects of sulprostone on the formation of
InsP3 and cytosolic Ca2+ levels in IMCD cells.
Fig. 8A shows that AVP and the
muscarinic receptor/Gq-stimulating agonist carbachol induced
statistically significant 1.4- and 2.4-fold increases in
InsP3 respectively; in contrast, sulprostone failed to
induce InsP3 formation in IMCD cells. Cytosolic
Ca2+ was imaged in single, fura-2-loaded IMCD cells (data not
shown). In agreement with other reports
(Nasrallah et al., 2001
;
Lorenz et al., 2003
), AVP,
sulprostone and PGE2 induced a small rise in cytosolic
Ca2+ (from about 50 nM to less than 200 nM) in a small number of
IMCD cells tested (2.4, 1.4 and 1.4%, respectively;
Fig. 8B). Preincubation of
cells with SC19220 invariably abolished the elevation of cytosolic
Ca2+ in response to sulprostone or PGE2, indicating that
the cytosolic Ca2+ signals resulted from EP1 receptor
stimulation (see Introduction). The data suggest that EP3 receptor
stimulation does not induce the formation of InsP3 or an
increase in cytosolic Ca2+ in IMCD cells. Thus, Ca2+ is
not involved in EP3 receptor-mediated stimulation of Rho and
inhibition of the AVP-induced AQP2 shuttle.
|
![]() |
Discussion |
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|
The EP3 receptor-induced activation of RhoA in IMCD cells is,
most likely, mediated by the G proteins G12/13
(Namba et al., 1993;
Hasegawa et al., 1997
;
Katoh et al., 1996
;
Nakamura et al., 1998
;
Yamaguchi et al., 2000
;
Hatae et al., 2002
).
G12/13 directly activate Rho guanine nucleotide exchange factors
(RhoGEFs, e.g. p115) which in turn activate RhoA
(Wells et al., 2002
). Neither
cAMP nor Ca2+ are involved in this pathway. In contrast, the
inhibition of RhoA through V2 receptors most likely involves cAMP. AVP
stimulates cAMP synthesis and subsequent activation of PKA which may
phosphorylate Rho (Lang et al.,
1996
; Forget et al.,
2002
). We have recently shown that the forskolin-induced AQP2
shuttle in CD8 cells (see Introduction) is accompanied by RhoA
phosphorylation, a decrease in RhoA activity, and an increased interaction of
RhoA with Rho guanine nucleotide dissociation inhibitor [RhoGDI
(Tamma et al., 2003
)], the
protein that terminats Rho activity
(Forget et al., 2002
).
Accordingly, activation of RhoA via G12/13 following the
stimulation of EP3 receptors and inhibition of RhoA by
cAMP-dependent phosphorylation, following the stimulation of V2 receptors, are
most likely the pathways for the bidirectional control of RhoA in IMCD
cells.
The mechanism by which activated Rho and its effectors inhibit AVP-induced
AQP2 translocation apparently involves the F-actin cytoskeleton. F-actin, in
particular subapical F-actin, also referred to as the terminal web, has a
barrier function in many exocytic processes. Its disintegration is considered
a prerequisite for exocytosis in various cell types including chromaffin
cells, mast cells and pancreatic acinar cells
(Valentijn et al., 1999).
Similarly, the F-actin network (stress fibers) in IMCD cells may function as a
physical barrier which hinders AQP2-bearing vesicles reaching the plasma
membrane. Several lines of evidence support this view. Activation of RhoA
via EP3 receptors or expression of constitutively active
RhoA lead to the formation of stress fibers and inhibited AVP-induced AQP2
translocation in IMCD cells [see above and Klussmann et al.
(Klussmann et al., 2001b
)].
Effectors of activated Rho that promote the formation of stress fibers are the
Rho kinases (Tapon and Hall,
1997
). Inhibition of Rho kinases with the inhibitor Y-27632
reduces the content of stress fibers in IMCD and CD8 cells and induces
translocation of AQP2 independently of cAMP elevation
(Klussmann et al., 2001b
;
Tamma et al., 2001
).
Similarly, depolymerization of stress fibers induced by cytochalasin D allows
AQP2 translocation without elevation of cAMP in IMCD and CD8 cells
(Klussmann et al., 2001b
;
Tamma et al., 2001
). In
addition to its barrier function, F-actin may directly interact with AQP2
(Brown et al., 1998
;
Umenishi et al., 2000
).
The inhibitory effect of PGE2 via EP3
receptors on AVP-induced increases in osmotic water permeability has been
ascribed to an inhibition of adenylyl cyclase activity
(Hebert, 1994;
Breyer and Breyer, 2001
).
However, pertussis toxin, an inhibitor of Gi, does not prevent
PGE2 antagonizing the effects of AVP in cultured rabbit cortical
collecting duct cells or in isolated rat outer medullary collecting ducts
(Noland et al., 1992
;
Aarab et al., 1993
;
Aarab et al., 1999
). In IMCD
and CD8 cells, pertussis toxin inhibits the AQP2 shuttle, presumably by
inhibition of Gi3 located on AQP2-bearing vesicles
(Valenti et al., 1998
).
Therefore, it cannot be used to test the involvement of adenylyl cyclase in
the inhibitory effect of sulprostone on the AQP2 shuttle. However, we show
here that EP3 receptor activation leads to inhibition of the AQP2
shuttle despite high levels of cAMP (Figs
6 and
7), strongly suggesting that
inhibition of adenylyl cyclase does not contribute to the diuretic effect.
Endothelin-1 and bradykinin antagonize AVP-induced antidiuresis by
stimulation of their cognate receptors (ETB- and B2
receptors respectively) located on principal cells (for a review, see
Klussmann et al., 2000).
ETB receptors couple to both the Gq/PLC system and
Gi/adenylyl cyclase; B2 receptors activate the
Gq/PLC system. Therefore, inhibition of cAMP synthesis and
elevation of cytosolic Ca2+ have been suggested to contribute to
the diuretic effects of these agents. However, both receptors also mediate Rho
activation (Gohla et al.,
1999
; Kitamura et al.,
1999
). In analogy to the EP3 receptor signaling, we
propose that diuretic receptors like ETB and B2
receptors exert their diuretic effects by activating the G12/13/Rho
pathway.
The identification of Rho and its effectors, the Rho kinases, as central
regulators of water reabsorption opens the door to new therapeutic concepts
for the treatment of diseases characterized by disturbed water homeostasis,
e.g. nephrogenic diabetes insipidus (NDI) or other diuretic states. Congenital
NDI is mainly caused by mutations in the V2 receptor
(Oksche and Rosenthal, 1998).
The inactivation of Rho or Rho kinases may induce the translocation of AQP2
independently of functional V2 receptors and thus reduce the loss of water.
Inhibitors of Rho kinases (Y-27632 and hydroxyfasudil) are currently being
tested or approved for the treatment of several diseases
(Wettschurek and Offermanns,
2002
). The use of these substances is limited owing to the fact
that they cannot be applied in a tissue-specific manner. An alternative
approach is the retrograde transfer of genes into the tubular system of the
kidney (Moullier et al.,
1994
). Candidate genes are dominant negative mutants of Rho or Rho
kinases under control of an inducible version of the collecting duct-specific
AQP2 promotor.
Our data suggest that the EP1 receptor antagonist SC19220
augments the inhibitory effects of sulprostone on AQP2 translocation and Rho
activity, implying that activation of the EP1 receptor reduces the
EP3 receptor-induced diuresis. EP1 receptors couple to
the Gq/PLC system; their activation results in the formation of
InsP3 with subsequent elevation of cytosolic
Ca2+ and generation of diacylglycerol (DAG) which in turn activates
PKC. Recently, it was shown that PKC causes F-actin disassembly through
activation of Src kinase, which in turn stimulates the Rho-specific
GTPase-activating protein p190, thereby inactivating Rho
(Brandt et al., 2002). In
addition, PKC phosphorylates G12, thereby attenuating its activity
(Fields et al., 1997). However, PKC activation via the PLC pathway is unlikely
to account for the EP1 receptor effect in IMCD cells, since
sulprostone does not induce the formation of InsP3 to a
detectable degree and mediates an increase of cytosolic Ca2+ in
only a minority of cells. It is possible that stimulation of other
phospholipases through EP1 receptors leads to activation of PKC.
For example, activation of phospholipase D results in the formation of
phosphatidic acid which is converted to DAG in a subsequent step
(Newton, 1995
;
Newton, 1997
).
In summary, our data indicate that the signal transduction pathway underlying the diuretic effect of PGE2 and possibly that of other diuretic agents includes Rho activation without the involvement of a cAMP- or Ca2+-dependent step. In addition, the data suggest that the pharmacological interference with the Rho pathway in principal cells is a strategy suitable for the treating diseases characterized by a disturbed water homeostasis.
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Acknowledgments |
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