1 Department of Pediatrics and 2 Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9063
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ABSTRACT |
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The present in
vitro microperfusion study examined the effect of luminal
angiotensin II on proximal convoluted tubule (PCT) volume absorption
and bicarbonate transport. Neither
1011 M,
10
10 M, nor 2 × 10
8 M luminal angiotensin
II significantly affected PCT transport. When tubules were first
perfused with enalaprilat to inhibit endogenous angiotensin II
production, addition of
10
10 M luminal angiotensin
II increased volume absorption (0.72 ± 0.08 vs. 0.86 ± 0.07 nl · mm
1 · min
1,
P < 0.01) and bicarbonate
transport (52.3 ± 3.7 vs. 67.9 ± 4.2 pmol · mm
1 · min
1,
P < 0.01). Addition of
10
6 M losartan, an
AT1 inhibitor, to the luminal
perfusate inhibited volume absorption (0.95 ± 0.14 vs. 0.72 ± 0.11 nl · mm
1 · min
1,
P < 0.05) and bicarbonate transport
(65.0 ± 7.3 vs. 54.7 ± 9.2 pmol · mm
1 · min
1,
P < 0.05). Addition of
10
4 M luminal PD-123319, an
AT2 inhibitor, was without effect.
In tubules perfused with
10
4 M luminal enalaprilat
and 10
4 M luminal
PD-123319, addition of 10
10
M luminal angiotensin II in the experimental period resulted in a
stimulation in volume absorption (0.61 ± 0.08 vs. 0.81 ± 0.10 nl · mm
1 · min
1,
P < 0.01) and bicarbonate transport
(49.9 ± 6.3 vs. 77.4 ± 14.3 pmol · mm
1 · min
1,
P < 0.01). In tubules perfused with
10
6 M losartan and
10
4 M enalaprilat, addition
of luminal 10
10 M
angiotensin II resulted in no change in transport. These data are
consistent with endogenous angiotensin II affecting PCT bicarbonate transport in vitro via luminal AT1
receptors.
in vitro microperfusion; angiotensin receptor; volume absorption; DuP-753; PD-123319; losartan
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INTRODUCTION |
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THE PROXIMAL TUBULE contains all the synthetic machinery to produce angiotensin II (3, 4, 14, 20, 23, 30). Angiotensinogen mRNA and protein are produced by the proximal tubule (14). Renin mRNA has been detected in primary cultures of rabbit proximal tubule cells using reverse transcription and polymerase chain reaction and in dissected proximal tubules from rabbits which received enalapril, an angiotensin converting enzyme inhibitor (23). Renin has also been found in cell lysates from rabbit proximal tubules in culture (23). Angiotensin converting enzyme activity is present on the brush border of the proximal tubule (20). Direct evidence for the production of angiotensin II by the proximal tubule has come from rat in vivo micropuncture and microperfusion studies, which have found luminal concentrations of angiotensin II ~100-fold higher than that in the plasma (3, 4, 30).
We have recently demonstrated that this endogenously produced angiotensin II modulates volume absorption in surface proximal convoluted tubules (PCT) of hydropenic rats (27). Thus, in the volume-depleted rat, angiotensin II acts in an autocrine or paracrine fashion to modulate proximal tubular transport. In this in vitro microperfusion study, we examined whether there was evidence that endogenously produced angiotensin II can affect PCT volume absorption and bicarbonate transport in nonsurface PCT perfused in vitro from euvolemic rabbits. In addition, we examined whether the endogenously produced angiotensin II effect was mediated via AT1 or AT2 receptors.
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METHODS |
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Midcortical and juxtamedullary rabbit PCT were dissected and perfused as previously described (1). Briefly, kidneys from adult female New Zealand White rabbits weighing 2-3 kg were cut in coronal slices. Individual tubules were dissected in cooled (4°C) Hanks' solution containing (in mM) 137 NaCl, 5 KCl, 0.8 MgSO4, 0.33 Na2HPO4, 0.44 KH2PO4, 1 MgCl2, 10 tris(hydroxymethyl)aminomethane hydrochloride, 0.25 CaCl2, 2 glutamine, and 2 L-lactate. Hanks' solution was bubbled with 100% O2 and had a pH of 7.4.
Tubules were perfused with an ultrafiltrate-like solution containing (in mM) 115 NaCl, 25 NaHCO3, 2.3 Na2HPO4, 10 sodium acetate, 1.8 CaCl2, 1 MgSO4, 5 KCl, 8.3 glucose, and 5 alanine and bathed in a similar solution containing 6 g/dl albumin. The perfusate and bath solutions were bubbled with 95% O2-5% CO2 and had a pH of 7.4. The osmolalities of the bath and perfusate were adjusted to 300 mosmol/kgH2O by the addition of either H2O or NaCl. To maintain the pH and bath osmolality constant, bath fluid was continuously changed at a rate of at least 0.5 ml/min. All tubules were perfused at ~10 nl/min at 38-39°C in a 1.2 ml temperature-controlled bath. The first period began after an equilibration time of 30-60 min. Subsequent periods were separated by an equilibration time of at least 15 min.
Net volume absorption
(JV,
nl · ml1 · min
1)
was measured as the difference between the perfusion
(V0) and collection
(VL) rates (nl/min) normalized
per millimeter of tubule length (L). Exhaustively dialyzed
[methoxy-3H]inulin
was added to the perfusate at a concentration of 50-75 µCi/ml,
so that the perfusion rate could be calculated. The collection rate was
measured with a 60-nl constant-volume pipette. The average tubule
length, measured using an eyepiece micrometer, was 1.4 ± 0.1 mm.
Total CO2 (TCO2)
measurements were performed using microcalorimetry
(Picapnotherm, model GVI; World Precision Instruments, New Haven, CT).
Net total CO2 flux
(JTCO2,
pmol · mm1 · min
1)
was calculated according to the equation:
JTCO2 = (V0C0
VLCL)/L,
where C0 and
CL represent the concentration of
TCO2 in the perfused and collected
fluid, respectively.
The transepithelial potential difference (in mV) was measured by using the perfusion pipette as the bridge into the tubular lumen. The perfusion and bath solutions were connected to the recording and reference calomel half-cells, respectively, via a bridge containing an ultrafiltrate of the bathing solution in series with a 3.6 M KCl/0.9 M KNO3 agarose bridge. The recording and reference calomel half-cells were connected to the high- and low-impedance side, respectively, of an electrometer (model 601; Keithley Instruments, Cleveland, OH).
There were at least four measurements of volume absorption and three of bicarbonate transport in a given period for each tubule. The mean values for individual periods in a given tubule were used to calculate the mean value for that period. Data are expressed as means ± SE. The t-test for paired data was used to determine statistical significance.
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RESULTS |
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Effect of luminal angiotensin II in absence and
presence of luminal enalaprilat on PCT volume absorption and
bicarbonate transport. The first series of experiments
was designed to examine whether luminal angiotensin II affected PCT
volume absorption or bicarbonate transport. The results are shown in
Table 1. In paired experiments, addition of
either 1010 M or
10
11 M angiotensin
II to the luminal perfusate, concentrations of angiotensin
II that have been previously shown to stimulate PCT volume absorption
when added to the bath (15, 29), had no effect on PCT volume
absorption. Similarly, addition of 2 × 10
8 M angiotensin II to the
lumen, a concentration measured in the rat PCT luminal fluid (4, 30),
also had no effect on the rate of volume absorption. There was a small
tendency of 10
10 M and 2 × 10
8 M luminal
angiotensin II to increase the rate of bicarbonate absorption (0.05 < P < 0.10).
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To determine whether the lack of an effect of exogenous angiotensin II
on PCT transport was due to endogenous angiotensin II production, we
examined the effect of 104
M luminal enalaprilat. As shown in Table 2,
addition of luminal enalaprilat, a converting enzyme inhibitor,
resulted in a small but not significant decrease in the rate of volume
absorption. However, addition of
10
4 luminal enalaprilat
significantly inhibited the rate of PCT bicarbonate absorption. These
data are consistent with endogenously produced angiotensin II affecting
PCT bicarbonate absorption.
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In the next series of experiments we examined whether luminal
1010 M angiotensin II would
affect the rate of PCT transport in the presence of
10
4 M enalaprilat. In these
experiments, tubules were perfused with an ultrafiltrate-like solution
containing enalaprilat in the control period for ~30 min prior to
measurement of volume absorption and bicarbonate transport. As shown in
Fig. 1, addition of
10
10 M luminal angiotensin
II increased both the rate of volume production and bicarbonate
absorption when the endogenous production of angiotensin II was blocked
with enalaprilat.
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Effect of losartan on PCT volume absorption and
bicarbonate transport. In the next series of
experiments we examined the effect of luminal
106 M losartan, an
AT1 antagonist, on proximal tubule
transport. As shown in Table 2 and Fig. 2,
addition of 10
6 M luminal
losartan resulted in an inhibition in both volume absorption and
bicarbonate transport with no effect on the transepithelial potential
difference. In this series of experiments there was a large variation
in the control rate of volume absorption and bicarbonate transport.
However, the reductions in volume absorption and bicarbonate transport
were statistically significant when analyzed in a paired fashion. These
data are consistent with endogenously produced angiotensin II
modulating PCT transport via a luminal AT1 receptor.
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To examine whether endogenous angiotensin II affected the
AT1 receptors on the basolateral
membrane, 106 M losartan
was added to the bathing solution. As shown in Table 2, bath losartan
had no effect on PCT transport. These data also indicate that losartan
is not having a nonspecific toxic effect on the tubule. In the final
period, we added 10
11 M
angiotensin II to the bathing solution in the presence of
10
6 M bath losartan. The
rates of volume absorption and bicarbonate transport were 1.12 ± 0.14 nl · mm
1 · min
1
and 83.3 ± 9.6 pmol · mm
1 · min
1,
respectively, in the presence of
10
6 M losartan and were
1.06 ± 0.14 nl · mm
1 · min
1
and 81.4 pmol · mm
1 · min
1
when 10
11 M angiotensin II
was added to the bathing solution. Thus the previously well-described
stimulation in PCT volume absorption by angiotensin II was blocked by
10
6 M losartan (12, 15,
29).
Finally, we examined whether the stimulation in volume absorption seen
with 1010 M luminal
angiotensin II in the presence of
10
4 M enalaprilat was
affected by 10
6 M luminal
losartan. In these experiments, tubules were perfused with
10
4 M enalaprilat and
10
6 M losartan in the
control period. In the experimental period, 10
10 M angiotensin II was
added to the luminal perfusate. As shown in Fig.
3,
10
6 M losartan blocked the
increase in transport previously found with angiotensin II in the
presence of enalaprilat. These data are consistent with luminal
angiotensin II mediating an increase in PCT transport via the
AT1 receptor.
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Effect of luminal PD-123319 on PCT volume absorption
and bicarbonate transport. In the next series of
experiments, we examined the effect of luminal
104 M PD-123319 on PCT
volume absorption and bicarbonate transport. As shown in Table 2,
addition of 10
4 M luminal
PD-123319 had no effect on PCT volume absorption, potential difference,
or rate of bicarbonate transport. Finally, we examined the effect of
10
10 M angiotensin II in
the presence of 10
4 M
PD-123319 and 10
4 M
enalaprilat. As shown in Fig. 4,
10
4 M PD-123319 did not
inhibit the luminal angiotensin II-mediated increase in bicarbonate
absorption on volume absorption in the presence of enalaprilat. These
data are consistent with the absence of a significant role for the
AT2 receptor in mediating the
effect of luminal angiotensin II.
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DISCUSSION |
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Angiotensin II plays an important role in modulating proximal tubule transport (2, 8, 11-13, 15, 19, 21, 22, 27-29, 31, 32). Systemic infusion of angiotensin II at doses that do not affect glomerular hemodynamics or blood pressure results in a significant increase in proximal tubule transport (17, 18). A reduction in angiotensin II levels by the systemic infusion of an angiotensin-converting enzyme inhibitor or administration of angiotensin II receptor antagonist produces a reduction in proximal tubule transport (8, 13, 18, 31, 32). Both in vivo and in vitro microperfusion studies demonstrate that physiological concentrations of peritubular angiotensin II increase proximal tubule transport (12, 15, 29).
A significant role for luminal angiotensin II to modulate proximal tubule transport seemed unlikely. Most studies found that luminal perfusion with angiotensin II produced either no effect or a trivial increase in proximal tubule transport (12, 16, 17, 27). Any filtered angiotensin II would be quickly hydrolyzed by enzymes on the brush-border membrane (25, 26). However, recent studies provide evidence for the local production and luminal secretion of angiotensin II by the PCT, which maintains a luminal concentration higher than that in the systemic circulation along the proximal tubule (3, 4, 30).
A previous in vitro rabbit microperfusion study examined the effect of
luminal angiotensin II on volume absorption (15). Li et al. (15) found
that addition of 1011 M,
but not 10
12 or
10
10 M, angiotensin II
stimulated volume absorption. They also found that addition of
10
8 M angiotensin II to the
luminal perfusate inhibited volume absorption to a rate not different
from zero. Our results are at significant variance from these. We found
that in the absence of enalaprilat, addition of luminal angiotensin II
at 10
11 M,
10
10 M, and 2 × 10
8 M had no significant
effect on the rate of volume absorption. The higher concentrations
produced a small increase in the rate of bicarbonate absorption that
did not reach statistical significance (0.05 < P < 0.10). The cause for the
discrepancy between these results is unclear.
The absence of an effect of addition of exogenous luminal angiotensin
II in vitro could be due to endogenous production of angiotensin II as
has been found in the rat (3, 4, 30). To examine the effect of
inhibition of angiotensin II production on proximal tubule transport we
used enalaprilat. Luminal enalaprilat at
104 M resulted in an
inhibition in PCT bicarbonate reabsorption; the small decrease in
volume absorption did not reach significance. The reason why
enalaprilat did not inhibit volume absorption is not clear.
Angiotensin- converting enzyme inhibitors may be affecting proximal
tubule transport by a secondary mechanism in addition to decreasing
angiotensin II production. A significant decrease in both volume
absorption and bicarbonate transport were observed with blockade of the
AT1 receptor by the addition of
luminal losartan. Furthermore, addition of
10
10 M angiotensin II to
the luminal perfusate in the presence of enalaprilat resulted in a
significant increase in both volume absorption and bicarbonate
transport. The ~20% decrease in volume absorption with luminal
losartan and ~20% increase in volume absorption with luminal
angiotensin II in the presence of enalaprilat are consistent with
comparable regulation of proximal tubule transport by luminal and
peritubular angiotensin II in the rabbit (29). Taken together, our data
are consistent with endogenous production of angiotensin II by the
proximal tubule. The lack of an effect of exogenous luminal angiotensin
II is consistent with ongoing in vitro production by the in vitro
perfused proximal tubule.
Angiotensin II binding sites are abundant along the nephron, with the
highest density in the PCT (24). The proximal tubule has angiotensin II
receptors on the apical and basolateral membrane (5-7, 9, 10).
Whether AT1 or
AT2 receptors would mediate any
luminal effect of angiotensin II was unclear. Dulin et al. (10)
described angiotensin II receptors on both the apical and basolateral
membrane. They found no evidence for apical membrane AT1 receptors in the rabbit.
125I-labeled saralasin was
displaced with high concentrations of AT2 receptor antagonists (10). On
the other hand, Burns et al. (7) found that
106 M losartan displaced
over 90% of labeled
125I-angiotensin II from
brush-border membrane vesicles and found no evidence for apical
membrane AT2 receptors. Our data
is consistent with the presence of
AT1 receptors mediating the
luminal effect of angiotensin II on proximal tubule transport. We found
that addition of losartan inhibited PCT bicarbonate transport and
volume absorption. The increase in PCT transport in the presence of
luminal enalaprilat by 10
10
M luminal angiotensin II was not seen when losartan was in the luminal
perfusate. On the other hand, the
AT2 inhibitor PD-123319 had no
effect on volume absorption and bicarbonate transport when added to the
luminal perfusate. In addition, the angiotensin II-mediated increase in
PCT transport in the presence of enalaprilat was observed in the
presence of the AT2 antagonist
PD-123319.
Several studies have shown that angiotensin II stimulates the Na+/H+ antiporter (2, 11, 28). This may be mediated by G protein activation of phospholipase A2 (21). Our data are consistent with the activation of the Na+/H+ antiporter by endogenously produced angiotensin II. We found that addition of enalaprilat and losartan inhibited the rate of bicarbonate reabsorption in the absence of a change in the transepithelial potential difference. Furthermore, addition of luminal angiotensin II in the presence of enalaprilat resulted in an electroneutral stimulation in bicarbonate reabsorption. Thus luminal angiotensin II is likely an important regulator of proximal tubule bicarbonate reabsorption.
In summary, our data are consistent with the presence of endogenously produced angiotensin II affecting PCT bicarbonate absorption from euvolemic rabbits. This effect is mediated entirely via the AT1 receptor.
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ACKNOWLEDGEMENTS |
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We are grateful for the able secretarial assistance of Janell McQuinn.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-41612 (to M. Baum) and KO8-DK-02232 (to R. Quigley), by a grant from the American Heart Association (to A. Quan), and by the National Kidney Foundation, Texas Affiliate (to M. Baum and A. Quan).
Address for reprint requests: M. Baum, Dept. of Pediatrics, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9063.
Received 26 February 1997; accepted in final form 19 June 1997.
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