(Hypertension. 1995;25:1008-1013.)
© 1995 American Heart Association, Inc.
Articles |
Effect of Inhibiting Renal Kallikrein on Prostaglandin E2, Water, and Sodium Excretion
From the Hypertension and Vascular Research Division, Department of Medicine and Heart and Vascular Institute, and the Division of Biostatistics and Research Epidemiology (E.P.), Henry Ford Hospital, Detroit, Mich.
Correspondence to Oscar A. Carretero, MD, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202-2689.
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Abstract To test the hypothesis that renal kinins act as natriuretic and diuretic hormones, we examined the effect of inhibiting glandular kallikrein on renal function in normotensive unanesthetized rats during normal sodium intake. To inhibit kallikrein at both the luminal and basolateral sides of the distal nephron, we used Fab fragments of monoclonal antibodies to rat urinary kallikrein (Fab-kallikrein). Fab fragments have advantages over intact IgG: they are filtered through the glomerulus and reach the lumen of the distal nephron, where kallikrein is localized and urinary kinins are released. Furthermore, the Fab fragment–antigen complex does not activate the complement system, avoiding the side effects associated with intact antibodies. Fab-kallikrein effectively blocked generation of kinins in the nephron lumen, decreasing urinary kininogenase activity (kallikrein) by 74% to 85% and kinin excretion by 76% to 79%. Fab-kallikrein induced a 30% decrease in urine volume and a 20% to 40% decrease in urinary sodium excretion but did not alter blood pressure, glomerular filtration rate, or renal blood flow. Although urinary prostaglandin E2 excretion also tended to decrease, this change was slower and of lesser magnitude than those of kinin and kininogenase excretion and did not attain statistical significance after Bonferroni's correction. In controls injected with either vehicle or Fab fragments of monoclonal antibodies to ricin (a vegetable protein not present in mammals), none of these parameters decreased significantly. We conclude that renal kinins participate in the short-term regulation of water and sodium excretion in normotensive unanesthetized rats, acting as diuretic and natriuretic hormones. Kinins acting on the distal nephron, either directly or via release of nitric oxide and/or prostaglandins, are likely responsible.
Key Words: kallikrein • kallikrein-kinin system • prostaglandins • sodium • body water • kidney function
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Introduction |
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Kinins administered into the renal artery cause diuresis and natriuresis1 2 ; however, they do not mimic the effects of endogenous kinins, which appear to act primarily as autocrine/paracrine hormones in the distal nephron. Renal kallikrein is synthesized and secreted by the connecting cells of the distal nephron, where it releases kinins from kininogen (which is found in the principal cells of the collecting duct) and/or plasma kininogen filtered through the glomeruli.3 4 Kinins in the distal nephron could play a role in the regulation of water and sodium excretion, either directly or through the release of prostaglandins and/or endothelium-derived relaxing factor (EDRF).5 6 7 8
When renal kinins are increased by treatment with mineralocorticoids, angiotensin-converting enzyme inhibitors, or metalloendopeptidase-24.11 inhibitors, they act as diuretic and natriuretic paracrine hormones; urinary kinins, urine volume, and sodium excretion increase, which can be partially blocked by inhibiting the renal kallikrein-kinin system.9 10 11 12 However, it is not known whether kinins also act as diuretic/natriuretic hormones when they are present in basal concentrations in untreated normotensive animals. Bradykinin analogues with antagonist properties have been used to block the effect of kinins.13 Nakagawa et al9 reported that infusion of one such kinin antagonist failed to alter water or sodium excretion in normotensive rats, and we have confirmed these findings (unpublished results). Since kinin receptor antagonists are kinin analogues, they can be destroyed by peptidases (kininases) in the proximal tubule14 15 ; thus, they may not reach the lumen of the distal nephron, where kinins are released, their receptors are localized, and part of the effect of kinins on water and sodium reabsorption occurs.16 17
To inhibit renal kallikrein at both the luminal and basolateral sides of the nephron, we used Fab fragments of IgG from a monoclonal antibody to urinary kallikrein (Fab-kallikrein).18 Fab fragments are distributed rapidly in the extracellular space, filtered through the glomerulus, and eliminated in the urine; hence, they reach both the basolateral and luminal sides of the distal nephron.19 20 Furthermore, the Fab fragment–antigen complex does not activate the complement system, thus avoiding the side effects associated with intact antibodies; moreover, the antibodies are quite specific, acting only on the antigen or closely related molecules.18 In this study, we tested the hypothesis that renal kinins act as natriuretic and diuretic hormones, investigating the effect of Fab-kallikrein on renal function in normotensive unanesthetized rats with moderate volume expansion.
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Methods |
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Preparation of Monoclonal Antibodies and Fab Fragments
Our method of producing monoclonal antibodies to rat glandular kallikrein was described previously.18 To control for nonspecific reactions, we used a monoclonal antibody to ricin (a vegetable protein not found in mammals) that was produced by a hybridoma (ATCC CRL 1758, American Type Culture Collection). Intact IgG was isolated from antibodies in murine ascites by immunoaffinity on immobilized protein A. Fab fragments were released from intact IgG by papain digestion, and Fab fragments were purified as described previously.10
Renal Function
Male Sprague-Dawley rats weighing 250 to 320 g
(Charles River Laboratories, Wilmington, Del) were maintained at
constant room temperature with a 12-hour light/dark cycle and fed
normal rat chow (Ralston Purina) containing 0.4% sodium and 2%
potassium with free access to water. They were acclimated to the
laboratory environment by being placed in a restraining cage for 4
hours on at least 3 different days. Unless otherwise indicated,
surgical procedures were performed with the animals under sodium
pentobarbital anesthesia (50 mg/kg IP). First, chronic catheters were
implanted in the bladder using a modification of the previously
described technique.10 21 Seven days later, a Doppler flow
probe was placed around the left renal artery after the surrounding
connective tissue had been removed. The flow probe cables were secured
subcutaneously and the ends of the connectors externalized dorsally.
Rats were treated with 200 000 U/kg IM penicillin G (Wyeth)
immediately after surgery and allowed to recover for 7 days, at which
time they showed normal feeding and grooming behavior. They were then
anesthetized with ether, and PE-10 catheters (Clay-Adams) fused to a
PE-50 tube (Clay-Adams) were placed in the abdominal aorta and inferior
vena cava via the left femoral artery and vein and tunneled
subcutaneously to the back of the neck. The catheters were filled with
heparinized saline (100 U/mL) and sealed with wire. The animals were
allowed to recover for 2 days before the experiment. Hemodynamics and
renal function were evaluated in awake rats. The arterial catheter was
connected to a transducer (Gould Statham) for measurement of mean
arterial blood pressure (BP). The Doppler flow probe was connected to a
pulse Doppler flowmeter (University of Iowa) for measurement of renal
blood flow (RBF), which was monitored on a Brush recorder (Gould
Instruments) connected to a computer (Heathkit).
Food was withheld overnight before the experiment, but water was allowed ad libitum. On the day of the experiment, each rat was placed in a restraining cage, and BP and RBF were monitored continuously. All protocols consisted of an equilibration period, a control period, and two experimental periods. Two hours before the experiment (equilibration period), an infusion of 0.15 mol/L NaCl solution (100 µL/min) was started via the inferior vena cava catheter and continued throughout the experiment using an infusion pump (model 990, Harvard Apparatus). When glomerular filtration rate (GFR) was measured, the infusion was changed to saline containing [3H]inulin (2.5 µCi/mL) (NEN) 60 minutes before the start of the control period. During each control and experimental period, urine was collected continuously via the bladder catheter and used to determine urine volume (UV), osmolarity, urinary sodium excretion (UNaV), urinary potassium excretion (UKV), urinary kinin excretion, kallikrein activity, and prostaglandin E2 (PGE2) and [3H]inulin concentrations. At the midpoint of each clearance period, 70 µL of blood was drawn from the arterial catheter for measurement of hematocrit and [3H]inulin concentration.
Experimental Protocols
Protocol 1
Rats were prepared as described above except that a Doppler flow
probe was not implanted. In this protocol, we examined whether Fab
fragments of monoclonal antibodies against kallikrein or ricin have any
effect on urinary kininogenase activity, kinin excretion, water
excretion, UNaV, UKV, and BP in normotensive
conscious rats. A 120-minute equilibration period was followed by a
30-minute control and two 30-minute experimental clearance periods.
Rats were divided into three groups: (1) Fab-kallikrein (n=9):
Fab-kallikrein was injected as a bolus (0.5 mg per rat in 500 µL
saline) via the venous catheter at the beginning of the first
experimental period, followed by a constant infusion of 8.3 µg/min
(in 100 µL saline) throughout the experiment. The total dose was 1 mg
per rat. (2) Fab-ricin (n=8): This was similar to the previous group
except that the rats received Fab-ricin instead of Fab-kallikrein. (3)
Time controls (n=6): This was similar to the previous groups except
that the rats received the same volume of 0.15 mol/L NaCl instead of
Fab fragments.
Protocol 2
In this protocol, we examined the effect of higher doses of
Fab-kallikrein (2 mg dissolved in 1 mL saline), with the total amount
being given as a bolus intravenous injection. In addition to UV,
UNaV, kininogenase activity, and kinin excretion, we also
measured PGE2 excretion, GFR, RBF, and BP. A 120-minute
equilibration period was followed by a 40-minute control period and two
40-minute experimental clearance periods. The collection time was
increased from 30 to 40 minutes so that enough volume was available to
facilitate the above determinations. Rats were divided into three
groups: (1) Fab-kallikrein (n=11): Fab-kallikrein was injected as a
bolus (2 mg per rat) via the venous catheter at the start of the
first experimental period. Rats were divided into two subgroups; RBF
and GFR were measured in one group (n=6) and urinary PGE2
excretion in the other (n=5). (2) Fab-ricin (n=13): This was similar to
the previous group except that the rats received Fab-ricin instead of
Fab-kallikrein. Renal function was measured in seven rats and
PGE2 in six. (3) Time controls (n=5): Rats were prepared in
the same manner and given equal volumes of normal saline. Only renal
function was determined in this group.
Analytical Methods
Urine samples were collected in a tube in an ice-cold bath.
Immediately after each experimental period, samples were mixed well and
aliquots (0.5 mL) placed in separate tubes, one of which contained 100
mmol/L EDTA (Fisher) with 10 mmol/L 1,10-phenanthroline (Fisher) as a
kininase inhibitor. Aliquots (1.0 mL) were placed in a tube containing
1N HCl for measurement of PGE2.
UV was determined gravimetrically and factored per 100 g body weight (milliliters per hour per 100 g body weight). UNaV and UKV were measured with a NOVA-1 ion electron autoanalyzer (Nova Biochemical) and expressed as microequivalents per hour per 100 g body weight. Urine osmolarity was determined with a freezing-point osmometer (Advanced Instruments). [3H]Inulin in urine and plasma was measured with a scintillation counter (Packard). GFR was calculated as the urine-to-plasma ratio of inulin multiplied by urine flow and expressed as milliliters per 100 g body weight. The change in RBF shown by the Doppler flowmeter was expressed as percent change from the control period.
Urinary kininogenase excretion (urinary kallikrein) was determined as described previously22 and expressed as nanograms kinin production per minute of incubation per hour of urine collection per 100 g body weight.
For urinary kinin excretion, the samples containing the kininase inhibitor were stored at -20°C until assay. Urinary kinin concentration was measured by radioimmunoassay as described previously.22 Kinin excretion was expressed as nanograms immunoreactive kinin per hour per 100 g body weight. When 20 ng lysyl-bradykinin was added to the fresh urine samples, bradykinin recovery was 91.5±3.1% (n=5).
For urinary PGE2 excretion, PGE2 was extracted
from rat urine. Sep-Pak C18 cartridges (Waters Associates) were
pretreated with 5 mL 100% methanol followed by 10 mL distilled water.
A 1.0-mL urine sample containing 0.5 mL of 1N HCl (pH
3) was applied
to the cartridge and washed with 10 mL distilled water.
PGE2 was eluted with 3.0 mL ethyl formate (Eastman Kodak).
The extract was evaporated to dryness under a nitrogen stream at room
temperature and stored at -20°C. For measurement of PGE2
concentration, the residue was reconstituted with assay buffer and
PGE2 determined by radioimmunoassay as described
previously.23 Urinary excretion of PGE2 was
expressed as nanograms immunoreactive PGE2 per hour per 100
g body weight. PGE2 recovery was assayed by addition of 10
ng PGE2 to five rat urine samples and found to be
88±6%.
Data Analysis
Values are expressed as mean±SEM. The control period was
compared with experimental periods 1 and 2 using either Student's
paired t test or Wilcoxon's signed rank test for markedly
non-normal distribution of data. These tests were done separately
within each of the three groups. Bonferroni's adjustment for multiple
comparisons within a group set the probability value for significance
at .025. Results with probability values between .025 and .05 were
considered suggestive.
Fab-ricin and Fab-kallikrein groups were compared independently for experimental periods 1 and 2. ANCOVA was used; covariants were the values observed during the control period. A log transformation was used to correct for non-normally distributed data or heterogeneous variances. Bonferroni's correction was used to adjust for multiple testing.
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Results |
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Protocol 1
In the Fab-kallikrein group, urinary kinin excretion decreased by 52% during the first experimental period and 79% during the second. These changes were highly significant compared with the control period, or the corresponding period in the group treated with Fab-ricin. Kininogenase activity was also lower in the Fab-kallikrein group. These parameters did not change significantly in either the Fab-ricin or time control group. BP did not change significantly in any group (Fig 1, Table 1).
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In the Fab-kallikrein group, UV and UNaV decreased only during the second experimental period; UV fell by 29% and UNaV by 25%, significantly less than in the Fab-ricin group. In the Fab-ricin and time control groups, UV and UNaV did not change significantly (Fig 1, Table 2). Urinary osmolarity tended to increase in the Fab-kallikrein group and decrease in the time control and Fab-ricin groups, but the changes were not statistically significant after Bonferroni's correction. There were no differences in UKV between the Fab-kallikrein, Fab-ricin, and time control groups; UKV decreased in all three groups, suggesting that changes in UKV are related to time rather than treatment (Fig 1, Tables 1 and 2).
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Protocol 2
Neither vehicle, Fab-ricin, nor Fab-kallikrein caused significant
changes in BP, GFR, or RBF (Table 3). In the
Fab-kallikrein group, as in the previous protocol, urinary kininogenase
and kinin excretion decreased during both experimental periods, whereas
UV fell only during the second period. Unlike the previous protocol,
UNaV also fell during the first experimental period (Fig 2,
Tables 4 and 5). During
the second experimental period, urinary PGE2 excretion fell
by 50% compared with the control period, although the change was not
statistically significant; however, it was lower in the Fab-kallikrein
group than in the Fab-ricin group (P=.03). Kininogenase
activity and kinin excretion were lower in the Fab-kallikrein group
than in the Fab-ricin group during both experimental periods. UV and
UNaV were lower in the Fab-kallikrein group than in the
Fab-ricin group during the second period. UKV decreased
significantly in the Fab-kallikrein group; however, in the Fab-ricin
group it also decreased significantly during the first experimental
period, suggesting (as in protocol 1) that changes in UKV
are related to time rather than treatment (Table 5).
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Discussion |
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We investigated the effect of Fab-kallikrein on renal function in normotensive unanesthetized rats with moderate volume expansion. We found that Fab fragments against urinary kallikrein decreased excretion of urinary kininogenase, kinins, UV, and UNaV without altering RBF or GFR. Neither vehicle nor Fab-ricin caused a significant decrease in these variables, indicating that these effects are not time-related but rather are specific for Fab-kallikrein. Our data support the hypothesis that renal kinins, acting as diuretic and natriuretic hormones, regulate UV and UNaV. We omitted anesthesia to avoid any untoward effects on renal hemodynamics or water and sodium excretion. Since kinins are probably released by renal kallikrein at both the basolateral and luminal sides of the distal nephron,24 25 we used Fab-kallikrein to inhibit kinin formation on both sides. As a control, we used Fab fragments of a monoclonal antibody to ricin; our purpose was to have a control group as close to Fab-kallikrein as possible but without the capacity to inhibit renal kallikrein, since Fab fragments could have some nonspecific effect when filtered by the glomerulus.
Fab-kallikrein significantly decreased both urinary kininogenase activity and kinin excretion. Since urinary kinins are formed mainly in the distal nephron, these results indicate that Fab-kallikrein is effective in blocking renal kallikrein in the lumen of the distal nephron. Although there is indirect evidence that urinary kinins are released by renal kallikrein, kinins could be generated by filtered plasma kallikrein or other proteases; thus, these results demonstrate that kinins are generated by an enzyme of the kallikrein family with very high homology and high kininogenase activity,26 in all likelihood renal kallikrein.
Urinary PGE2 excretion decreased during the second experimental period. Furthermore, differences from the control period or the second experimental period of the Fab-ricin group were suggestive but did not attain statistical significance after Bonferroni's correction, probably because of the variability of the data and the small number of urine samples. The changes in PGE2 excretion were likely secondary to the decrease in kinins, since there is evidence that exogenously administered bradykinin stimulates the release of PGE2 by the kidney; however, there is little information on the role of endogenous kinins in the control of renal PGE2.7 27 28 The decrease in PGE2 was slower to develop than that of urinary kinins; one explanation may be that kinins stimulate the release of PGE2 by increasing intracellular calcium and activating phospholipases,29 30 31 changes whose effects could take longer to dissipate. Whether PGE2 mediates some of the observed changes in water and sodium excretion cannot be asserted based on this study. PGE2 in the distal nephron may inhibit sodium and water reabsorption, in the latter case by antagonizing the effect of antidiuretic hormone32 33 ; however, these results are not universal, especially in the rat,34 so it could be that kinins inhibit water and sodium transport either directly or via the release of other mediators such as nitric oxide.5
In both protocols, Fab-kallikrein caused a significant decrease in UV and UNaV. In the second protocol, we doubled the dose of Fab-kallikrein to see whether the effect would be increased. Although kininogenase excretion decreased further in the second protocol, it was difficult to arrive at a conclusion because kininogenase excretion in the rat is highly variable. The decrease in urinary kinins was greater during the first experimental period in rats receiving a higher amount of Fabkallikrein. Similarly, both UV and UNaV decreased more rapidly in the second group; the drop in UNaV was statistically significant during both experimental periods (Fig 2, Table 5). The decreases in UV and UNaV were in the range of 20% to 30% of basal excretion; although this can be considered modest, the differences are important because, if sustained, a 20% to 30% retention of water and sodium would take only a few days to produce edema or hypertension. BP, RBF, and GFR were not altered by Fab-kallikrein, indicating that changes in water and sodium excretion are not secondary to hemodynamic alterations; however, there is evidence that kinins participate in the regulation of papillary blood flow.35 36 Thus, some of the effects we observed could be due to subtle changes in blood flow distribution. UKV decreased not only in the Fab-kallikrein but also the Fab-ricin group, suggesting that this effect is related to time rather than to treatment. Osmolarity tended to increase in the Fab-kallikrein group and decrease in controls, suggesting that this effect is treatment-related; however, the changes were not statistically significant after Bonferroni's correction.
In vivo studies involving injection of bradykinin into the renal artery clearly indicate that kinins (like most vasodilators) cause natriuresis and diuresis because of changes in renal interstitial fluid pressure.1 2 In addition, studies both in vivo and in vitro have shown that the natriuretic and diuretic effects of exogenous bradykinin seen after inhibition of prostaglandin synthesis are mediated by EDRF.5 8 Taken together, these studies suggest that exogenously administered kinins inhibit water and/or sodium transport, and that their effect is mediated in part by prostaglandins and EDRF. Whether endogenous kinins act on both the luminal and/or basolateral side of the nephron is not well established. Localization studies indicate that in addition to the luminal kallikrein-kinin system in the distal nephron, kallikrein or a kallikrein-like enzyme located on the basolateral side is released into the interstitial-vascular compartment of the kidney24 25 37 ; thus, kinins may also be released in this compartment. In vitro studies support the possibility that kinins can have an effect on both the basolateral and/or luminal sides of the nephron.38 39 40 41 42 43 Our findings suggest that in normotensive unanesthetized rats, simultaneous blockade of kinins at both basolateral and luminal surfaces is necessary to decrease diuresis and natriuresis, since kinin antagonists (which act only on the basolateral side of the nephron) do not lower water and sodium excretion in normotensive animals.9 However, it is also possible that only luminal blockade of kinins is required. In deoxycorticosterone acetate– treated rats, we found that blockade of kinins with Fab fragments of kinin antibodies or a kinin receptor antagonist decreased diuresis, whereas only Fab fragments decreased natriuresis, also suggesting that intraluminal kinins have a natriuretic effect while basolateral kinins may regulate diuresis.10 27 41 42
In conclusion, various studies have shown that kinins act as natriuretic and diuretic hormones when their concentration is increased by blocking hydrolysis with angiotensin-converting enzyme and/or neutral endopeptidase-24.11 inhibitors or in rats treated with mineralocorticoids.9 10 11 However, we believe our study is the first to show that in normotensive unanesthetized rats, kinins participate in the regulation of water and sodium excretion. The diuretic and natriuretic actions of renal kinins may occur directly or via the release of nitric oxide and/or prostaglandins at the level of the distal nephron.
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Acknowledgments |
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This work was supported by grant HL-28982 from the National Institutes of Health, Bethesda, Md.
Received August 1, 1994; first decision September 8, 1994; accepted January 11, 1995.
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