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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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 (108 M in the
bath) inhibits HCO
3 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;
10
8 M), the major
P-450 metabolite in the MTAL,
inhibited HCO
3 absorption, whereas
pretreatment with 20-HETE prevented the inhibition by ANG II. The
addition of 15-HETE (10
8 M)
to the bath had no effect on HCO
3
absorption. The inhibition of HCO
3
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 HCO
3 absorption by 35%,
suggesting that NO directly regulates MTAL
HCO
3 absorption. Addition of
10
11 to
10
10 M ANG II to the bath
did not affect HCO
3 absorption. We
conclude that ANG II inhibits HCO
3
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 HCO
3
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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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
HCO
3 in the MTAL is mediated by apical
membrane
Na+/H+
exchange (23). Furthermore, the regulation of MTAL
HCO
3 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 HCO
3 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 HCO
3 absorption
in the MTAL. Infusion of ANG II into rats was associated with an
increase in HCO
3 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
HCO
3 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
HCO
3 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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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 HCO
3, 2.0 Ca2+, 1.5 Mg2+, 2.0 phosphate, 1.2 SO2
4, 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.
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RESULTS |
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Effects of ANG II on HCO3
Absorption
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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 HCO
3 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 10
4 M
furosemide in the tubule lumen, addition of
10
8 M ANG II to the bath
decreased HCO
3 absorption from 12.9 ± 1.6 to 8.4 ± 2.1 pmol · min
1 · mm
1
(n = 3;
P < 0.05; Fig.
1B). Thus the inhibition of
HCO
3 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
(10
12 to
10
10 M) stimulate, whereas
high concentrations (10
8 to
10
6 M) inhibit absorption
(28, 33, 57). To determine whether a biphasic response was present for
the regulation of HCO
3 absorption in
the MTAL, we examined the effects of low concentrations of ANG II.
Addition of either 10
11 or
10
10 M ANG II to the bath
had no effect on HCO
3 absorption
[13.5 ± 1.2 pmol · min
1 · mm
1
for control vs. 13.4 ± 1.2 pmol · min
1 · mm
1
for ANG II; n = 4;
P = not significant (NS)]. Thus
we found no evidence for biphasic regulation of
HCO
3 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 HCORole 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 HCO
3
absorption in the MTAL by increasing cell cAMP, an effect that is
maximal with an AVP concentration of
10
10 M (18). The results in
Fig.
2A
show that, in tubules bathed with
10
10 M AVP, addition of
10
8 M ANG II to the bath
decreased HCO
3 absorption from 8.0 ± 1.5 to 4.4 ± 0.9 pmol · min
1 · mm
1
(n = 3;
P < 0.05). Thus the inhibitory
effects of ANG II and AVP were additive, suggesting that ANG II
inhibits HCO
3 absorption via a
signaling pathway independent of cAMP.
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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
HCO
3 absorption by ANG II was examined
using staurosporine and chelerythrine chloride, inhibitors of PKC that
selectively abolish PKC-dependent regulation of
HCO
3 absorption in the MTAL (21, 22).
The results in Fig. 3 show that, in tubules
bathed with 10
7 M
staurosporine or 10
7 M
chelerythrine chloride, addition of ANG II to the bath decreased HCO
3 absorption from 10.8 ± 1.6 to
6.0 ± 1.3 pmol · min
1 · mm
1
(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 10
8 M ANG II to
the bath decreased HCO
3 absorption from 13.7 ± 1.5 to 9.6 ± 1.3 pmol · min
1 · mm
1
(n = 4;
P < 0.005). These data suggest that
NO is not involved in the ANG II-dependent inhibition of
HCO
3 absorption. Addition of 1 mM
L-NAME alone to the bath had no
effect on HCO
3 absorption (15.1 ± 2.2 pmol · min
1 · mm
1
in control vs. 14.6 ± 1.7 pmol · min
1 · mm
1
in L-NAME; n = 3; P = NS).
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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
10
8 M ANG II to the bath
had no effect on HCO
3 absorption (10.9 ± 1.5 pmol · min
1 · mm
1
in ETYA vs. 11.1 ± 1.1 pmol · min
1 · mm
1
in ETYA + ANG II; n = 3; P = NS). These data
suggest that metabolism of AA plays an important role in the inhibition
of HCO
3 absorption by ANG II. Addition
of ETYA alone to the bath decreased the basal
HCO
3 absorption rate slightly
(~20%, control vs. ETYA; Fig.
5A).1
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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
HCO
3 absorption, tubules were bathed
with genistein or herbimycin A, inhibitors that selectively block
tyrosine kinase-dependent regulation of
HCO
3 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
10
8 M ANG II to the bath
decreased HCO
3 absorption by only
17%, from 17.2 ± 0.6 to 14.4 ± 0.5 pmol · min
1 · mm
1
(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
HCO
3 absorption by ANG II.
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DISCUSSION |
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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
Previous studies in the proximal tubule have demonstrated a
dose-dependent, biphasic response to ANG II, with low concentrations (1012 to
10
10 M) stimulating volume
and HCO
3 absorption and high
concentrations (10
8 to
10
6 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 HCO
3 absorption in the MTAL: 5 × 10
9 to
10
8 M ANG II inhibited
HCO
3 absorption, whereas 10
11 to
10
10 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
HCO
3 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 HCO
3 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
HCO
3 reabsorption measured for the
surface loop segment as a whole. When this is considered along with our observation that ANG II directly inhibits
HCO
3 absorption in the MTAL, it
appears likely that the stimulation of
HCO
3 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
HCO
3 absorption (16, 58). Our results
establish, however, that the increase in
HCO
3 absorption observed in the
surface loop segment in vivo is unlikely to be the result of a direct
stimulation of HCO
3 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
HCO
3 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 HCORole 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 HCO
3
absorption is abolished by ODYA, a highly selective inhibitor of
cytochrome P-450 enzymes (39, 60);
2) addition of 20-HETE inhibits
HCO
3 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 HCO
3
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
HCO
3 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
HCO
3 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
HCO
3 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 HCO
3 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
HCO
3 absorption by ANG II in the MTAL.
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 HCO
3 absorption. We
found no role for NO in mediating the inhibition of
HCO
3 absorption by ANG II. However, we
discovered that NO itself appears to be a potent stimulator of MTAL
HCO
3 absorption. Specifically, we
found that HCO
3 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
HCO
3 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
HCO
3 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 HCO
3 absorption in
the MTAL.
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 HCO ![]() |
ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-38217 (to D. W. Good).
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FOOTNOTES |
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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 HCO
3 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
HCO
3 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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