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3
absorption via a cytochrome
P-450-dependent pathway in
MTAL
Departments of Medicine and of Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The role of ANG II in the regulation of ion reabsorption by the
renal thick ascending limb is poorly understood. Here, we demonstrate
that ANG II (10
8 M in the
bath) inhibits HCO3 absorption by 40%
in the isolated, perfused medullary thick ascending limb (MTAL) of the
rat. The inhibition by ANG II was abolished by pretreatment with
eicosatetraynoic acid (10 µM), a general inhibitor of arachidonic acid metabolism, or 17-octadecynoic acid (10 µM), a highly selective inhibitor of cytochrome P-450
pathways. Bath addition of 20-hydroxyeicosatetraenoic acid (20-HETE;
108 M), the major
P-450 metabolite in the MTAL,
inhibited HCO3 absorption, whereas
pretreatment with 20-HETE prevented the inhibition by ANG II. The
addition of 15-HETE (108 M)
to the bath had no effect on HCO3
absorption. The inhibition of HCO3
absorption by ANG II was reduced by >50% in the presence of the
tyrosine kinase inhibitors genistein (7 µM) or herbimycin A (1 µM).
We found no role for cAMP, protein kinase C, or NO in the inhibition by
ANG II. However, addition of the exogenous NO donor
S-nitroso-N-acetylpenicillamine (SNAP; 10 µM) or the NO synthase (NOS) substrate
L-arginine (1 mM) to the bath
stimulated HCO3 absorption by 35%,
suggesting that NO directly regulates MTAL
HCO3 absorption. Addition of
1011 to
1010 M ANG II to the bath
did not affect HCO3 absorption. We
conclude that ANG II inhibits HCO3
absorption in the MTAL via a cytochrome
P-450-dependent signaling pathway, most likely involving the production of 20-HETE. Tyrosine kinase pathways also appear to play a role in the ANG II-induced transport inhibition. The inhibition of HCO3
absorption by ANG II in the MTAL may play a key role in the ability of
the kidney to regulate sodium balance and extracellular fluid volume independently of acid-base balance.
20-hydroxyeicosatetraenoic acid; tyrosine kinases; nitric oxide; signal transduction; acid-base regulation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ANGIOTENSIN II (ANG II) participates in the regulation
of renal sodium and water excretion through a variety of physiological mechanisms. These include effects on renal hemodynamics and glomerular filtration rate, regulation of aldosterone secretion, and direct effects on renal tubule transport through interactions with membrane receptors (7, 26, 28). In addition to its effects to promote renal
sodium retention, ANG II stimulates
H+ secretion and
HCO3 reabsorption in both proximal and
distal tubules (16, 17, 32, 34, 38, 57, 58), regulates
H+-ATPase activity in the cortical
collecting duct (53), and influences the production and secretion of
ammonium by proximal tubule segments (12, 41). These findings suggest
that, in addition to its more clearly defined role in the control of
sodium excretion and extracellular fluid volume, ANG II also may
influence urinary net acid excretion and participate in the regulation
of acid-base balance.
Several recent findings suggest that the thick ascending limb of the loop of Henle is a target site for ANG II-dependent regulation in the kidney. First, the thick ascending limb expresses ANG II receptors (5, 40, 44). Second, ANG II has been shown to influence the activity of apical membrane K+ channels (36) and 86Rb uptake (15) in isolated thick ascending limb segments. Third, ANG II has been reported to regulate a variety of signaling pathways in thick ascending limbs, including intracellular Ca2+ activity, NO production, protein kinase C (PKC) activity, and metabolism of arachidonic acid (AA) (3, 5, 15, 36). These studies indicate that ANG II can influence thick ascending limb function. However, the effects of ANG II on transepithelial ion reabsorption by the thick ascending limb have not been examined and the importance of various signal transduction pathways in mediating ANG II-induced effects on transepithelial transport is not understood.
The medullary thick ascending limb (MTAL) of the rat participates in
the renal regulation of acid-base balance by reabsorbing much of the
filtered HCO3 that escapes the
proximal tubule (19). Absorption of
HCO3 in the MTAL is mediated by apical
membrane
Na+/H+
exchange (23). Furthermore, the regulation of MTAL
HCO3 absorption is achieved primarily
through regulation of this apical exchanger (19, 20, 23). Studies in
both proximal and distal tubules have shown that ANG II
stimulates HCO3 absorption through the
stimulation of apical membrane
Na+/H+
exchange (7, 17, 28, 34, 38, 58). These findings suggest that ANG II
may regulate apical
Na+/H+
exchange activity and HCO3 absorption
in the MTAL. Infusion of ANG II into rats was associated with an
increase in HCO3 absorption by the
loop segment, the portion of the nephron between the late proximal
convoluted tubule and early distal tubule (9). However, no studies have
examined directly the effects of ANG II on
HCO3 absorption by the thick ascending limb.
The present study was designed to examine the effects of ANG II on
HCO3 absorption by the MTAL of the rat and to identify signal transduction pathways involved in ANG
II-dependent regulation. The results demonstrate that ANG II inhibits
HCO3 absorption in the MTAL via a
cytochrome P-450-dependent signaling pathway. This inhibition may play an important role in the ability of
the kidney to regulate sodium and volume balance independently of
acid-base balance.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Materials.
17-Octadecynoic acid (ODYA) was purchased from Biomol (Plymouth
Meeting, PA), 20-hydroxyeicosatetraenoic acid (20-HETE) was from
Cayman Chemical (Ann Arbor, MI), and
S-nitroso-N-acetylpenicillamine (SNAP) was from Calbiochem (La Jolla, CA). ANG II,
N-nitro-L-arginine methyl ester (L-NAME),
L-arginine,
15(S)-hydroxyeicosatetraenoic acid
(15-HETE), 5,8,11,14-eicosatetraynoic acid (ETYA); and palmitic acid
were obtained from Sigma Chemical (St. Louis, MO). ANG II was prepared
as a 4 × 104 M stock
solution in H2O. Stock solutions
(10 mM) of ODYA, ETYA, and palmitic acid were prepared in ethanol,
20-HETE and 15-HETE were purchased as stock solutions in ethanol, and
SNAP was prepared as a 10 mM stock solution in dimethyl sulfoxide. The
agents were diluted into bath solutions to final concentrations given
in RESULTS. Equal concentrations of
ethanol or dimethyl sulfoxide were added to control solutions.
Solutions containing other experimental agents were prepared as
previously described (18, 20, 21).
Tubule perfusion.
Male Sprague-Dawley rats (50-100 g body wt; Taconic, Germantown,
NY) were allowed free access to autoclaved food (NIH 31 diet; Ralston
Purina, St. Louis, MO) and water up to the time of experiments. MTAL
were isolated and perfused in vitro, as previously described (18,
20). In brief, tubules were dissected from the inner stripe of the
outer medulla at 10°C in control bath solution (see below),
transferred to a bath chamber on the stage of an inverted microscope,
and mounted on concentric glass pipettes for microperfusion at
37°C. The length of the perfused segments ranged from 0.49 to 0.64 mm. In all experiments, the lumen and bath solutions contained (in mM)
146 Na+, 4 K+, 122 Cl, 25 HCO3, 2.0 Ca2+, 1.5 Mg2+, 2.0 phosphate, 1.2 SO24, 1.0 citrate, 2.0 lactate,
and 5.5 glucose. In most experiments, the bath also contained 0.2%
fatty acid-free bovine albumin. However, for protocols involving fatty
acids (ETYA, ODYA, palmitic acid, 20-HETE, and 15-HETE), albumin was
omitted from the bath solutions to prevent binding and inactivation of
the experimental lipids. All solutions were equilibrated with 95%
O2-5%
CO2 and ranged between pH 7.45 and 7.47 at 37°C. Bath solutions were delivered to the perfusion
chamber via a continuously flowing exchange system (18). Experimental agents were added to the bath and lumen solutions as described in
RESULTS.
3 absorption was as described
previously (18, 20). The tubules were equilibrated for 20-30 min
at 37°C in the initial perfusion and bath solutions, and the
luminal flow rate (normalized per unit tubule length) was adjusted to
1.5-2.0
nl · min1 · mm1.
Two or three 10-min tubule fluid samples were then collected for each
period (initial, experimental, and recovery). The tubules were allowed
to reequilibrate for 5-15 min after an experimental agent was
added to or removed from the bath solution. The absolute rate of
HCO3 absorption
(JHCO3,
pmol · min1 · mm1)
was calculated from the luminal flow rate and the difference between
total CO2 concentrations measured
in perfused and collected fluids (18). An average
HCO3 absorption rate was calculated
for each period studied in a given tubule. When repeat measurements
were made at the beginning and end of an experiment (initial and
recovery periods), the values were averaged. Single tubule values are
presented in Figs. 1-7. Mean values ± SE
(n = no. of tubules) are presented in
the text. Differences between means were evaluated using the Student's
t-test for paired data, with
P < 0.05 considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of ANG II on HCO3
Absorption
3
absorption by the MTAL is shown in Fig.
1A.
Addition of 108 M ANG II to
the bath decreased HCO3 absorption by
40%, from 14.6 ± 0.5 to 8.8 ± 1.1 pmol · min1 · mm1
(n = 5;
P < 0.005). The inhibition was
observed within 15 min after the addition of ANG II to the bath
solution and was reversible. ANG II at 5 × 109 M induced a similar
inhibition of HCO3 absorption (data
not shown).
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One possible explanation for the inhibition of
HCO3 absorption is that it occurs as
the indirect result of an effect of ANG II on transport pathways
involved in transcellular NaCl absorption. For example, ANG II-induced
stimulation of apical membrane
Na+-K+-2Cl
cotransport or K+ channel activity
may increase intracellular Na+
activity (3, 15, 36), an effect that could secondarily reduce the
driving force for apical membrane
Na+/H+
exchange and decrease HCO3 absorption.
To test this possibility, we examined the effect of ANG II in tubules perfused with furosemide to inhibit net NaCl absorption (18). In MTAL
studied with 104 M
furosemide in the tubule lumen, addition of
108 M ANG II to the bath
decreased HCO3 absorption from 12.9 ± 1.6 to 8.4 ± 2.1 pmol · min1 · mm1
(n = 3;
P < 0.05; Fig.
1B). Thus the inhibition of
HCO3 absorption occurs independently
of effects of ANG II on net NaCl absorption.
In the proximal tubule, ANG II regulates volume and
HCO3 absorption in a
concentration-dependent manner: low concentrations
(1012 to
1010 M) stimulate, whereas
high concentrations (108 to
106 M) inhibit absorption
(28, 33, 57). To determine whether a biphasic response was present for
the regulation of HCO3 absorption in
the MTAL, we examined the effects of low concentrations of ANG II.
Addition of either 1011 or
1010 M ANG II to the bath
had no effect on HCO3 absorption
[13.5 ± 1.2 pmol · min1 · mm1
for control vs. 13.4 ± 1.2 pmol · min1 · mm1
for ANG II; n = 4;
P = not significant (NS)]. Thus
we found no evidence for biphasic regulation of
HCO3 absorption by ANG II in the MTAL.
Signaling Pathways Involved in Inhibition by ANG II
Previously, we demonstrated that cAMP, PKC, and tyrosine kinase pathways play key roles in the regulation of MTAL HCO3 absorption (18, 20-22). We
therefore examined the importance of these and other signaling pathways
for regulation by ANG II.
Role of cAMP.
cAMP inhibits HCO3 absorption in the
MTAL (18). To determine whether cAMP is involved in the inhibition by
ANG II, we examined the interaction between ANG II and arginine vasopressin (AVP). AVP inhibits HCO3
absorption in the MTAL by increasing cell cAMP, an effect that is
maximal with an AVP concentration of
1010 M (18). The results in
Fig.
2A
show that, in tubules bathed with
1010 M AVP, addition of
108 M ANG II to the bath
decreased HCO3 absorption from 8.0 ± 1.5 to 4.4 ± 0.9 pmol · min1 · mm1
(n = 3;
P < 0.05). Thus the inhibitory
effects of ANG II and AVP were additive, suggesting that ANG II
inhibits HCO3 absorption via a
signaling pathway independent of cAMP.
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3 absorption (18). The results in
Fig. 2B show that, in the presence of
106 M forskolin or
104 M 8-BrcAMP, addition of
108 M ANG II to the bath
decreased HCO3 absorption from 8.3 ± 0.9 to 4.2 ± 1.0 pmol · min1 · mm1
(n = 4;
P < 0.005). Together, these results
establish that the inhibition of HCO3
absorption by ANG II is not mediated by an increase in cAMP.
Role of PKC.
PKC has been suggested to play a role in ANG II-dependent regulation of
HCO3 transport in the proximal tubule (28, 35, 57). The role of PKC in the inhibition of
HCO3 absorption by ANG II was examined
using staurosporine and chelerythrine chloride, inhibitors of PKC that
selectively abolish PKC-dependent regulation of
HCO3 absorption in the MTAL (21, 22).
The results in Fig. 3 show that, in tubules
bathed with 107 M
staurosporine or 107 M
chelerythrine chloride, addition of ANG II to the bath decreased HCO3 absorption from 10.8 ± 1.6 to
6.0 ± 1.3 pmol · min1 · mm1
(n = 4;
P < 0.01). Thus the inhibition by
ANG II does not involve PKC.
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Role of NO.
Recent studies suggest that stimulation of apical membrane
K+ channels by ANG II in the MTAL
is mediated by NO (36). To examine the role of NO in the ANG II-induced
inhibition of HCO3 absorption, we
performed two series of experiments. In the first series, MTAL were
bathed with the NOS inhibitor
L-NAME at a concentration that
completely eliminated the NO-dependent effect of ANG II on K+ channel activity (1 mM) (36).
The results in Fig.
4A show
that, in the presence of L-NAME,
addition of 108 M ANG II to
the bath decreased HCO3 absorption from 13.7 ± 1.5 to 9.6 ± 1.3 pmol · min1 · mm1
(n = 4;
P < 0.005). These data suggest that
NO is not involved in the ANG II-dependent inhibition of
HCO3 absorption. Addition of 1 mM
L-NAME alone to the bath had no
effect on HCO3 absorption (15.1 ± 2.2 pmol · min1 · mm1
in control vs. 14.6 ± 1.7 pmol · min1 · mm1
in L-NAME; n = 3; P = NS).
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3 absorption of two compounds that
generate NO: the NOS substrate
L-arginine and the exogenous NO
donor SNAP (51). As shown in Fig. 4B,
addition of either 1 mM
L-arginine or 10 µM SNAP to
the bath reversibly increased HCO3 absorption from 10.8 ± 1.0 to 14.8 ± 1.0 pmol · min1 · mm1
(n = 8;
P < 0.001). Addition of 1 mM
D-arginine to the bath had no
effect on HCO3 absorption (data not
shown). Thus agents that generate NO stimulate
HCO3 absorption in the MTAL, an effect
opposite to the inhibition observed with ANG II. Taken together, these
results indicate that the inhibition of
HCO3 absorption by ANG II is not
mediated by NO.
Role of cytochrome P-450 and 20-HETE.
Recent studies indicate that the metabolism of AA via cytochrome
P-450 pathways plays a role in the
regulation of NaCl absorption in the MTAL (14, 24, 59). To determine
whether the metabolism of AA is involved in ANG II inhibition of
HCO3 absorption, we examined the
effect of ETYA, a general inhibitor of AA metabolic pathways (10). The
results in Fig.
5A show
that, in MTAL bathed with 10 µM ETYA, addition of
108 M ANG II to the bath
had no effect on HCO3 absorption (10.9 ± 1.5 pmol · min1 · mm1
in ETYA vs. 11.1 ± 1.1 pmol · min1 · mm1
in ETYA + ANG II; n = 3; P = NS). These data
suggest that metabolism of AA plays an important role in the inhibition
of HCO3 absorption by ANG II. Addition
of ETYA alone to the bath decreased the basal
HCO3 absorption rate slightly
(~20%, control vs. ETYA; Fig.
5A).1
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3 absorption
(11.0 ± 0.3 pmol · min1 · mm1
in ODYA vs. 10.9 ± 0.5 pmol · min1 · mm1
in ODYA + ANG II; n = 3;
P = NS). To determine whether this may have been the result of a nonspecific effect of ODYA as a fatty acid,
additional experiments were performed using palmitic acid, a fatty acid
analog of ODYA that is inactive as a
P-450 inhibitor (60). The results in
Fig. 5C show that palmitic acid (10 µM in the bath) did not prevent the inhibition of
HCO3 absorption by ANG II (11.5 ± 1.2 pmol · min1 · mm1
in palmitic acid vs. 7.4 ± 0.8 pmol · min1 · mm1
in palmitic acid + ANG II; n = 3;
P < 0.05). Neither ODYA nor palmitic
acid alone affected HCO3 absorption (Fig. 5, B and
C). These results indicate that ANG
II inhibits HCO3 absorption via a
cytochrome P-450-dependent pathway.
To define further the involvement of the cytochrome
P-450 pathway in
HCO3 transport regulation, we examined the effects of 20-HETE, the major
P-450 metabolite of AA in the MTAL
(11, 14, 36). If ANG II inhibits HCO3 absorption by increasing the production of 20-HETE, then pretreatment with 20-HETE should prevent ANG II-induced inhibition, and the addition
of 20-HETE alone should inhibit HCO3 absorption. The results in Fig.
6A show
that, in tubules bathed with
108 M 20-HETE, addition of
108 M ANG II to the bath
had no effect on HCO3 absorption (11.2 ± 0.5 pmol · min1 · mm1
in 20-HETE vs. 11.2 ± 0.4 pmol · min1 · mm1
in 20-HETE + ANG II; n = 4;
P = NS). The results in Fig.
6B show that the addition of
108 M 20-HETE to the bath
solution decreased HCO3 absorption
from 13.2 ± 1.2 to 9.6 ± 1.1 pmol · min1 · mm1
(n = 4; P < 0.005). The inhibition by 20-HETE
was selective for this metabolite because bath addition of 15-HETE,
another endogenously produced HETE (59), had no effect on
HCO3 absorption (11.4 ± 2.0 pmol · min1 · mm1
in control vs. 11.5 ± 2.2 pmol · min1 · mm1
in 15-HETE; n = 3;
P = NS; Fig.
6C).2
These results demonstrate that 20-HETE inhibits
HCO3 absorption in the MTAL and that
the inhibitory effects of ANG II and 20-HETE are not additive. Taken
together, our data support the conclusion that ANG II inhibits
HCO3 absorption via a cytochrome
P-450-dependent pathway that involves
the production of 20-HETE.
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Role of tyrosine kinase pathways.
Tyrosine kinase pathways play a key role in the regulation of MTAL
HCO3 absorption (20, 22) and have been
implicated in signal transduction by ANG II in cultured proximal tubule
and mesangial cells (37, 54). To examine whether tyrosine kinase
pathways are involved in the inhibition of
HCO3 absorption, tubules were bathed
with genistein or herbimycin A, inhibitors that selectively block
tyrosine kinase-dependent regulation of
HCO3 absorption in the MTAL (20, 22). The results in Fig. 7 show that, in the
presence of 7 µM genistein or 1 µM herbimycin A, addition of
108 M ANG II to the bath
decreased HCO3 absorption by only
17%, from 17.2 ± 0.6 to 14.4 ± 0.5 pmol · min1 · mm1
(n = 5;
P < 0.005). This decrease is less
than half that observed under identical conditions in the absence of
the inhibitors (P < 0.025;
Fig. 1A), indicating that the
tyrosine kinase inhibitors partially block ANG II action. These results
suggest that tyrosine kinase pathways play a role in the inhibition of
HCO3 absorption by ANG II.
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DISCUSSION |
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|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The role of ANG II in the regulation of ion reabsorption by the thick
ascending limb is poorly understood. The present study demonstrates
that ANG II directly inhibits HCO3 absorption in the MTAL of the rat. This inhibition is mediated via a
cytochrome P-450-dependent signaling
pathway that likely involves the production of 20-HETE. Tyrosine kinase
pathways also appear to play a role in the ANG II-induced transport
inhibition. As discussed below, the effect of ANG II to decrease
luminal acidification in the MTAL may play an important role in
preserving acid-base balance when sodium intake and extracellular fluid
volume are changed.
ANG II Inhibits
HCO3 Absorption in the
MTAL
3 absorption to a similar extent in the absence and presence of luminal furosemide, which indicates that the inhibition occurs independent of effects on net NaCl
absorption and likely is mediated through regulation of transporters
directly involved in transcellular
HCO3 absorption. In the MTAL, apical
membrane
Na+/H+
exchange mediates virtually all of the
H+ secretion necessary for
HCO3 absorption (19, 23). Thus it is
very likely that ANG II inhibits apical
Na+/H+
exchange activity in the MTAL, an effect opposite to its physiological action to stimulate apical
Na+/H+
exchange and HCO3 absorption in the
proximal tubule and early distal tubule (16, 17, 28, 34, 38, 57, 58).
At this point, we do not know whether the ANG II signaling pathway is
coupled directly to inhibition of the apical Na+/H+
exchanger or if ANG II may act indirectly to reduce the activity of the
exchanger through effects on other transporters. In the proximal
tubule, ANG II increases HCO3
absorption by stimulating directly both apical membrane
Na+/H+
exchange and basolateral membrane
Na+-HCO3
cotransport (17). The basolateral HCO3 transporters involved in HCO3
absorption in the MTAL are not understood, but may include
Na+-HCO3
cotransport,
K+-HCO3
cotransport, and/or
Cl/HCO3
exchange (19). Further direct studies of the effects of ANG II on
apical membrane
Na+/H+
exchange activity and basolateral membrane
HCO3 efflux pathways are needed to
define the mechanism of HCO3 transport
inhibition in the MTAL.
Previous studies in the proximal tubule have demonstrated a
dose-dependent, biphasic response to ANG II, with low concentrations (1012 to
1010 M) stimulating volume
and HCO3 absorption and high
concentrations (108 to
106 M) inhibiting
absorption (28, 33, 57). A similar concentration dependence has been
reported in the MTAL for ANG II regulation of apical membrane
K+ channels (36),
86Rb uptake (15), and
Na+-K+-2Cl
cotransport activity (3). These biphasic responses appear to reflect
the activation by ANG II of multiple signal transduction pathways (15,
28, 33, 36). In contrast, we found no evidence for biphasic regulation
of HCO3 absorption in the MTAL: 5 × 109 to
108 M ANG II inhibited
HCO3 absorption, whereas 1011 to
1010 M ANG II had no
effect. Importantly, concentrations of ANG II measured in proximal
tubule fluid and star vessel plasma in the rat kidney cortex in vivo
ranged from 10 to 40 nM, values several orders of magnitude higher than
concentrations in systemic plasma (6, 42, 49). Furthermore, ANG II
levels in the renal medulla are even higher than those in the cortex
(42). Thus the concentrations of ANG II that inhibit
HCO3 absorption in the MTAL are
similar to ANG II levels measured in the renal medulla in vivo,
suggesting that the transport effects we observed represent physiologically relevant regulation.
In recent in vivo microperfusion studies, infusion of ANG II into rats
increased HCO3 absorption by the surface loop segment, the portion of the nephron between the late proximal convoluted tubule and early distal tubule (9). Based on this
observation, it has been inferred that ANG II stimulates HCO3 absorption in the thick ascending
limb (9, 15), a finding in apparent contrast to the results of the
present study. It is important to note, however, that the MTAL is short
in surface nephrons and does not contribute significantly to net
HCO3 reabsorption measured for the
surface loop segment as a whole. When this is considered along with our observation that ANG II directly inhibits
HCO3 absorption in the MTAL, it
appears likely that the stimulation of
HCO3 absorption by ANG II in the
surface loop may be due to effects on segments other than the thick
ascending limb. In particular, the stimulation may take place in the
proximal straight tubule and/or early distal tubule, segments in which ANG II has been demonstrated to increase
HCO3 absorption (16, 58). Our results
establish, however, that the increase in
HCO3 absorption observed in the
surface loop segment in vivo is unlikely to be the result of a direct
stimulation of HCO3 absorption by ANG
II in the MTAL.
Two pharmacologically distinct ANG II receptors,
AT1 and
AT2, have been identified and
cloned (25, 45). AT1 is the
predominant receptor type in the kidney and is thought to mediate most
of the effects of ANG II on transport in the proximal tubule (7, 8,
45). AT1 receptors also have been
localized to the thick ascending limb (5, 44). In recent preliminary
studies, we confirmed the expression of
AT1 receptors in the MTAL of the
rat and demonstrated that the inhibition of
HCO3 absorption by ANG II was blocked
by the AT1 receptor antagonist losartan (55). Thus the regulation of
HCO3 absorption by ANG II in the MTAL
likely is mediated through intracellular signals generated by the
interaction of ANG II with basolateral membrane
AT1
receptors.3
Signal Transduction by ANG II
Our results demonstrate that ANG II inhibits HCO3 absorption in the MTAL via
cytochrome P-450- and tyrosine kinase-dependent signaling pathways. In contrast, we found no role for
cAMP, PKC, or NO in mediating the ANG II-induced transport inhibition.
The lack of involvement of cAMP is noteworthy because the adenylyl
cyclase-protein kinase A pathway is believed to play an important role
in the regulation of apical membrane
Na+/H+
exchange and HCO3 absorption by ANG II
in the proximal tubule (7, 13, 28, 34). Thus our studies identify a
distinct difference in the signaling pathways that couple ANG II to the
regulation of HCO3 absorption in the proximal tubule and MTAL. An ancillary finding of our study is that NO
appears to be a potent stimulator of MTAL
HCO3 absorption. These findings are
discussed below in the context of current understanding of signal
transduction in the MTAL.
Role of cytochrome P-450 pathways in inhibition by
ANG II.
The metabolism of AA to biologically active products by cytochrome
P-450 enzymes plays a key role in the
regulation of a variety of renal processes, including vascular
resistance, tubuloglomerular feedback, and sodium reabsorption and
excretion (27, 29, 46). The MTAL has a high cytochrome
P-450 enzyme activity and has been identified as an important site of endogenous production of
P-450 metabolites, predominantly
20-HETE (11, 14, 36, 59). In the present study, we demonstrate that
inhibition of HCO3 absorption by ANG
II in the MTAL is mediated via a cytochrome P-450-dependent pathway that most
likely involves the production of 20-HETE. This conclusion is based on
several observations: 1) the ANG
II-induced inhibition of HCO3
absorption is abolished by ODYA, a highly selective inhibitor of
cytochrome P-450 enzymes (39, 60);
2) addition of 20-HETE inhibits
HCO3 absorption, whereas addition of
15-HETE has no effect; 3) the inhibitory effects of 20-HETE and ANG II are not additive, consistent with these factors decreasing HCO3
absorption via a common mechanism; and
4) ANG II increases the production of 20-HETE in isolated MTAL segments (36). Previous studies in rats
have demonstrated that endogenously produced 20-HETE inhibits net
chloride absorption by the loop segment in vivo (59) and the MTAL in
vitro (24). Our study identifies an additional physiological role for
P-450-derived 20-HETE in the MTAL,
namely, regulation of acid secretion and transepithelial
HCO3 absorption.
-hydroxylase product 20-HETE
in mediating ANG II inhibition of HCO3
absorption; however, other AA products that may affect ion transport
are influenced by ANG II in renal tubules. In a recent study in rat
MTAL suspensions, inhibition of
86Rb uptake by ANG II was mediated
through stimulation of PGE2
production via a cyclooxygenase pathway (15). However, it is unlikely
that this pathway is involved in ANG II-induced inhibition of
HCO3 absorption because
1) cyclooxygenase-dependent
production of PGE2 is not
inhibited by ODYA (39, 60), and 2)
PGE2 does not inhibit HCO3 absorption in the MTAL (21). In
the proximal tubule, production of epoxyeicosatrienoic acids (EETs) via
P-450 epoxygenases is increased by
ANG II (13, 43, 46), and EETs have been shown to influence
ion transport in proximal tubules and collecting ducts (13, 29, 46).
However, production of EETs is low in the MTAL and is not altered by
ANG II (11, 36). Also, EETs (5,6- and 11,12-EET) did not affect
chloride absorption or K+ channel
activity in isolated rat MTALs (24, 36). These findings suggest that
EETs are unlikely to be involved in the ANG II-dependent regulation of
HCO3 absorption. It should be noted,
however, that the MTAL produces other
P-450 metabolites, including 19-HETE
and 20-COOH-AA, the formation of which is inhibited by ODYA (11, 43,
60). We cannot rule out the possibility that one or more of these
products, in addition to 20-HETE, may contribute to the inhibition of
HCO3 absorption.
Although the mechanism by which cytochrome
P-450 pathways regulate
HCO3 absorption in the MTAL is not
known, some effects of P-450
metabolites on MTAL transport pathways have been described. 20-HETE
inhibits apical membrane
Na+-K+-2Cl
cotransport and K+ channel
activity in the MTAL (2, 14, 36), effects that likely mediate its
action to inhibit net chloride absorption (24, 59). As noted above,
however, we found that ANG II inhibits HCO3 absorption to a similar extent in
tubules perfused with and without furosemide to block
Na+-K+-2Cl
cotransport, indicating that the ANG II-induced
P-450 pathway inhibits
HCO3 absorption independent of effects on net chloride absorption. In segments of the proximal tubule and
collecting duct, 20-HETE has been shown to inhibit
Na+-K+-ATPase
activity (46-48). However, 20-HETE and 20-COOH-AA did not affect
Na+-K+
ATPase activity in MTAL suspensions (14), suggesting that inhibition of
the Na+ pump does not account for
ANG II-induced inhibition of HCO3 absorption. AA pathways have been suggested to play a role in mediating
cAMP-independent regulation of apical membrane
Na+/H+
exchange activity by ANG II in proximal tubule cells (13, 38). At
present, however, the role of cytochrome
P-450 pathways in the regulation of
Na+/H+
exchange in renal tubules is not understood. Thus direct studies of the
effects of P-450 metabolites on
Na+/H+
exchange activity in the MTAL will be important not only to understand the role of P-450 pathways in the
regulation of this transport process, but also to identify the
mechanism by which ANG II inhibits MTAL
HCO3 absorption.
Role of tyrosine kinase pathways in inhibition by
ANG II.
We have shown previously that tyrosine kinase pathways play a crucial
role in the regulation of HCO3
absorption by hyperosmolality and growth factors in the MTAL (20, 22). In the present study, the effect of ANG II to inhibit
HCO3 absorption was reduced by >50%
in the presence of genistein or herbimycin A, two chemically unrelated
tyrosine kinase inhibitors with different mechanisms of action (20).
Thus tyrosine kinases appear to be important components of the
signaling pathway through which ANG II inhibits
HCO3 absorption. Recent studies
indicate that tyrosine kinase pathways are involved in ANG II-induced
regulation of ion transport in mesangial cells (37) and OKP cells, a
proximal tubule cell line (54). In particular, in OKP
cells, the nonreceptor tyrosine kinase c-src appeared to play a role in
mediating ANG II regulation of NHE3 (54), the apical
Na+/H+
exchanger isoform that mediates H+
secretion and HCO3 absorption in the
MTAL and proximal tubule (1, 4, 20). Thus c-src may be a component of
the tyrosine kinase pathway involved in inhibition of
HCO3 absorption by ANG II in the MTAL.
3 absorption by ANG II likely
involves both cytochrome
P-450-dependent and tyrosine kinase
pathways. The observation that blocking the cytochrome
P-450 pathway with ODYA completely
eliminated the inhibition of HCO3
absorption indicates that signaling through the
P-450 pathway is necessary for
HCO3 transport regulation, and that
the ANG II-induced tyrosine kinase pathway is incapable of inhibiting
HCO3 absorption independent of the
cytochrome P-450 pathway. These
findings suggest that the cytochrome
P-450 and tyrosine kinase effectors
may lie within a single regulatory pathway. It is possible that
tyrosine kinases may be located upstream or downstream of cytochrome
P-450 enzymes in the ANG II-induced
signaling cascade. Alternatively, tyrosine kinases may be activated in
a parallel pathway that interacts with and modifies the activity of the
cytochrome P-450-dependent AA pathway.
Further work is needed to identify the tyrosine kinase(s) regulated by
ANG II in the MTAL and to understand the nature of the relationship
between the tyrosine kinase and cytochrome
P-450 signaling pathways.
NO stimulates
HCO3 absorption.
Based on the recent observation that NO was involved in stimulation of
apical membrane K+ channels by ANG
II in the rat MTAL (36), we investigated its possible role in the
regulation of HCO3 absorption. We
found no role for NO in mediating the inhibition of
HCO3 absorption by ANG II. However, we
discovered that NO itself appears to be a potent stimulator of MTAL
HCO3 absorption. Specifically, we
found that HCO3 absorption was
increased reversibly by the addition of either an exogenous NO donor or
the endogenous NO substrate
L-arginine. The latter result
suggests that the MTAL is capable of producing NO and that the locally
produced NO can act directly to regulate
HCO3 absorption. This conclusion is
supported by studies demonstrating that NOS isoforms are expressed in
MTAL segments (31) and that endogenous NO inhibits chloride absorption
in the microperfused rat cortical thick ascending limb (52). In
addition, NO has been reported recently to stimulate
HCO3 absorption in the proximal
convoluted tubule of the rat in vivo (56). Thus, although more
extensive studies clearly are needed, our results identify NO as a
factor that may be directly involved in the physiological control of
acid secretion and HCO3 absorption in
the MTAL.
3 absorption via the NO pathway
would oppose inhibition via the cytochrome
P-450 pathway. We found, however, that
the inhibition of HCO3 absorption by
ANG II was not potentiated in tubules pretreated with
L-NAME and that ODYA did
not unmask stimulation of HCO3 absorption by ANG II. These findings suggest either that ANG
II-induced production of NO is minimal under the conditions of our
experiments or that activation of the cytochrome
P-450 pathway may suppress the
stimulatory effect of NO.
Physiological Significance
Previously, we proposed that the MTAL plays an important role in the ability of the kidneys to maintain acid-base balance when sodium balance and extracellular fluid volume are altered (19). The results of the present study identify ANG II as a factor that may contribute to this process. Activation of the renin-angiotensin system in response to sodium and volume depletion results in several effects on renal acid-base transport: 1) direct stimulation of HCO3 absorption in
proximal and distal tubules by ANG II (16, 32, 34, 57, 58);
2) increased release of aldosterone,
which directly stimulates acid secretion by the collecting ducts (19);
and 3) stimulation of ammonium production by ANG II in the proximal tubule (12, 41). Other effects of
volume depletion, such as changes in hemodynamics and catecholamine
levels, also act to enhance proximal tubule
HCO3 absorption (50). Together, these
effects would act synergistically to increase urinary net acid
excretion and promote the development of metabolic alkalosis. We
suggest, however, that changes in acid excretion are minimized because
the above effects, which tend to increase urinary acidification, are
opposed by a decrease in luminal acidification along the MTAL, mediated
in part by the direct inhibitory action of ANG II. That is, when sodium
intake and extracellular fluid volume are decreased, the effect of ANG II to inhibit HCO3 absorption in the
MTAL would offset ANG II stimulation of
HCO3 absorption in the proximal and
distal tubules and aldosterone stimulation of
H+ secretion in the collecting
ducts to stabilize net acid excretion. When sodium intake and volume
are increased, net acid excretion would be maintained through changes
opposite to those described above. In this way, the direct action of
ANG II to inhibit HCO3 absorption in
the MTAL would play a key role in enabling the kidney to regulate
extracellular fluid volume independently of acid-base balance. Finally,
in addition to this physiological role, the inhibition of
HCO3 absorption by ANG II may contribute to changes in net acid excretion under pathophysiological conditions. For example, an increase in luminal acidification along the
MTAL mediated by a decrease in ANG II levels may contribute to the
metabolic alkalosis observed in primary hyperaldosteronism.
| |
ACKNOWLEDGEMENTS |
|---|
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-38217 (to D. W. Good).
| |
FOOTNOTES |
|---|
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. §1734 solely to indicate this fact.
2
The inhibition of
HCO3 absorption by exogenously added
20-HETE is not reversible within the relatively short time frame of in
vitro microperfusion studies (presumably because membrane association
and/or protein binding provides a continued source of intracellular
lipid). Thus the 15-HETE experiments not only establish the specificity
of the 20-HETE-induced transport inhibition, but also serve as time
controls for the 20-HETE experiments.
3
In the proximal tubule, ANG II influences ion
transport through interactions with either apical or basolateral
membrane AT1 receptors (7). In the
MTAL, addition of 108 M ANG
II to the lumen had no effect on HCO3 absorption (T. George and D. Good, unpublished observations). Thus, if
apical receptors for ANG II are present in the MTAL, then they have a
different concentration dependence than the basolateral receptors
and/or are coupled to signaling pathways that do not influence
HCO3 absorption.
1
The mechanism of the small inhibition of basal
HCO3 absorption by ETYA was not
investigated, but may relate to effects on an ODYA-insensitive AA
pathway and/or to a direct interaction with ion channels, as reported
in other systems (30).
Address for reprint requests and other correspondence: D. W. Good, Division of Nephrology, 4.200 John Sealy Annex, Univ. of Texas Medical Branch, Galveston, TX 77555.
Received 10 December 1998; accepted in final form 12 February 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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