A Peptide Released by Pepsin From Kininogen Domain 1 Is a Potent Blocker of ANP-Mediated Diuresis-Natriuresis in the Rat
Abstract A 20–amino acid peptide, KYEIKEGDCPVQSGKTWQDC (PU-D1), released by pepsin hydrolysis of LMW kininogen domain 1 was tested for its ability to antagonize the diuretic and natriuretic effect of ANP103-125 in anesthetized rats. A single dose of 10.8 or 21.6 pmol (25 or 50 ng) PU-D1 given intravenously or into the duodenal lumen suppressed the diuresis-natriuresis induced by 209 pmol (500 ng) ANP by 43% to 59% and 69% to 96%, respectively. None of the doses tested (2.16 to 432 pmol, 5 ng to 1 μg) modified systemic blood pressure. Strikingly, a single IV dose of 10.8 pmol PU-D1 blocked the action of ANP for more than 3 hours. ANP blockade by PU-D1 was annulled completely by the bradykinin (BK) B2 receptor inhibitor Hoe 140. On a molar basis, PU-D1 is more effective than BK and kinins of 15, 16, and 18 amino acids for blocking the ANP-mediated diuresis-natriuresis. As with BK and other kinins, the inhibitory effect of Pu-D1 on ANP is obtained only within a small range of picomol doses. A single dose of 2.16 or 4.32 pmol PU-D1 or 47 pmol (50 ng) BK is ineffective against ANP if injected alone. However, when both substances are administered concomitantly at these subthreshold doses, they totally suppress ANP-induced diuresis-natriuresis. These results raise the question of whether PU-D1, released from kininogen domain 1, either alone or associated with BK, may interact with ANP in the regulation of urinary water and electrolyte excretion in physiological and pathological conditions.
In 1953 we coined the name pepsanurin to designate a fragment, released by pepsin (pH 2.5) from partially purified plasma globulins, that was endowed with a potent antidiuretic action in normal hyper-hydrated rats.1 PU differed from vasopressin and pepsitensin,2 but neither its chemical structure nor the mechanism of action could be clarified. The discovery of the natriuretic peptide produced by the atria3 opened the possibility of exploring whether PU action was the result of antagonism on the cardiac peptide. This was indeed the case, as we demonstrated that PU inhibited the diuretic natriuretic effect of an ANP bolus.4 More recently we demonstrated that in anesthetized rats (0.190 to 0.220 kg) infused with isotonic glucose solution a single IV injection of 94.3 to 142 pmol (100 to 150 ng) BK inhibits sodium excretion promoted by a bolus of 209 pmol (0.5 μg) of ANP, whereas larger or smaller doses of BK were ineffective.5 This inhibitory effect on ANP renal excretory function was exerted only within a narrow dose range. Instead of increasing, the anti-ANP effect of BK vanished with larger doses: 236 to 472 pmol (250, 500 ng). The inhibition of ANP natriuretic- saluretic action by BK was also reproduced, at low doses (<1 nmol per rat) by kinins of 15, 16, and 18 amino acids,6 7 which are fragments of kininogens released by the hydrolytic action of pepsin.8 These peptides, as well as BK, lose their blunting action on ANP when Hoe 140, a blocker of BK B2 receptor, was given prior to kinin administration.5 6 7 Hoe 140 also prevented ANP inhibition produced by pepsin hydrolysates of dialyzed plasma,9 or a hydrolysate fraction obtained by the action of pepsin on purified LMW kininogen. From this later fraction we isolated and identified a 20–amino acid peptide with the sequence KYEIKEGDCPVQSGKTWQDC (MW 2314.87). This structure corresponds to a segment located in domain 1 of HMW and LMW kininogens, and its amino acid chain is extended from arginine-57 to cysteine-76. Because its effects are similar to those of a 15–amino acid kinin identified from PU, named PU-15,6 we have designated this peptide PU-D1. This compound, which has no common sequence with kinins, possesses the peculiar feature of kinins to block ANP-mediated diuretic-natriuretic action only in a small dose range. On a molar basis, it is 6- to 7-fold more potent than BK as an ANP blocker, and it induces a long-lasting anti-ANP effect. Like BK and other kinins, it loses its inhibitory activity if Hoe 140 is given prior to its administration. In this article we describe the most relevant properties of synthetic PU-D1, alone or associated with BK, as an inhibitor of the ANP-mediated effect on urinary volume and Na and K excretion in anesthetized rats.
ANP (ANP103-125, or atriopeptin II, rat form), BK, and pepsin from porcine stomach mucosa were purchased from Sigma Chemical Co. Hoe 140 was a gift of Hoechst, Frankfurt an Main, Germany. PU-D1 was synthesized by Bios Chile, Ingenieria Genética. CH3CN and TFA for HPLC and other chemicals of analytical level and chromatographic columns were purchased from Merck.
Preparation of PU-D1
The starting material was fresh human plasma obtained from the blood bank of the Hospital of Pontificia Universidad Católica de Chile. Plasma was processed immediately to obtain the kininogens, as described by Johnson et al.10 Following affinity chromatography on carboxymethyl papain Sepharose, kininogens were concentrated by ultrafiltration on Amicon PM-30 membrane and chromatographed on a semi-preparative HPLC ionic exchange DEAE column. The separated LMW kininogen was approximately 95% pure by SDS-PAGE and Western blot analysis and was submitted to the hydrolytic action of pepsin, at pH 2.5, 37°C for 4 hours. One mol of pepsin was added per 10 mol of kininogen. At the end of the incubation, the pH of the mixture was adjusted to 6.1, and after heating to 70°C for a few minutes it was centrifuged at 10 000g for 20 minutes. Adequate volumes of the supernatant were fractionated in Sep-Pak–C18 columns equilibrated with H2O and eluted in two steps with 2 mL of 15% CH3CN and 30% CH3CN in 0.1% TFA. Each collected fraction was lyophilized, resuspended, and tested in the bioassay described below. The material eluted by 30% CH3CN exhibited strong inhibition of ANP-stimulated urinary excretion, particularly on Na. Thereafter this fraction was purified and isolated using an HPLC Lichrocart 125-4 Supersphere 100 RP-18 column equilibrated with 7.5% CH3CN and 0.1% TFA. To obtain separation of the active compound, a gradient was employed from 5% CH3CN to 35% CH3CN in 0.1% TFA, with a flow rate of 1 mL/min. The total volume obtained was 60 mL. The fluids corresponding to the different peaks were lyophilized separately. The material showing the highest activity was submitted to an additional purification using a Hibar 250-4 Lichrosorb RP-18 column equilibrated with 7.5% CH3CN and 0.1% TFA. The sample was eluted using a gradient from 7.5% to 50% of CH3CN in 0.1% TFA with a flow rate of 1 mL/min. The corresponding chromatogram of the last fraction is shown in Fig 1⇓. The pure fraction was lyophilized and submitted to a sequence analysis at Bios Chile by Edmond degradation determining the N-terminus. The sequence KYEIKEGDCPVQSGKTWQDC was obtained and identified as corresponding to residues 57 to 76 of domain 1 of the heavy chain of human kininogens. Thereafter, this 20–amino acid peptide was synthetized using Fast-Moc chemistry in a commercially available peptide synthesizer (Applied Biosystems). The peptide is water soluble, colorless, and odorless, and its purity was characterized by compositional analysis (total HCl hydrolysis), mass spectroscopy, and sequencing.
Bioassay to Test the Anti-ANP Effects
A previously reported bioassay was used.3 4 5 6 8 All experimental procedures were in accordance with institutional and international guidelines for the welfare of animals. In brief, fasted adult female rats, body weight 0.235 ± 0.002 kg (mean±SEM) were anesthetized with sodium pentobarbital, 40 mg/kg IP, and heparinized. Polyethylene cannulas were inserted in a femoral artery, a jugular and femoral vein, and trachea. Arterial blood pressure was monitored by connecting a femoral artery to a transducer and a Grass polygraph. A constant infusion of IGS was started through the jugular vein (0.6 mL/h at time 0). Urine was collected during 10 periods of 20 minutes each by means of a silastic catheter introduced in the bladder. Two intravenous boluses of 209 pmol (0.5 μg) of ANP were administered at the start of the fourth and ninth periods. PU-D1 was given either IV or ID, 3 minutes and 40 minutes before the second ANP bolus, respectively. To inject ID, a small incision in the abdominal wall was performed ahead of time. PU-D1 was injected ID 2 to 5 cm from the pylorus. IGS was used as the vehicle for PU-D1, BK, and Hoe 140 throughout. All doses are expressed in pmol per rat. Urinary volume was determined gravimetrically, and Na and K levels were measured in an Eppendorf flame spectrophotometer. For a quantitative expression of the anti-ANP effects of PU-D1, the urinary excretion of sodium, potassium, and volume brought about by the second bolus of ANP were compared with the respective values following the first bolus, considered the control.
Effect of PU-D1 Given IV
Single injections of 2.16, 4.32, 10.8, 21.6, 43.2, 108, and 216 pmol (5, 10, 25, 50, 100, 250, and 500 ng) PU-D1 were assayed in order to obtain dose-response curves and to find the most effective dose of PU-D1 as an ANP blocking agent. Each dose dissolved in 50 μL of IGS was injected 3 minutes before the second ANP bolus. A control group received 50 μL IGS injected 3 minutes before the second ANP bolus.
Effect of PU-D1 Given ID
Single doses of 2.16, 4.32, 10.8, 21.6, and 108 pmol PU-D1 were given ID to test whether this peptide might reproduce the inhibitory effect of PU-15 given by this route.6 Each dose was injected in 250 μL of IGS, 40 minutes before the second ANP bolus.
Effect of Hoe 140 and Anti-ANP Action of PU-D1
Having evidence that the most effective dose of PU-D1 as an ANP blocker was 10.8 pmol (25 ng) per rat, we investigated whether a dose of 1.92 nmol per rat of Hoe 140 (2.5 μg) that abolished the anti-ANP effect of BK was able to counteract PU-D1, either given IV or ID. The effect of Hoe 140 was assayed in three groups of rats. In the first one, Hoe 140 and PU-D1 were administered IV 40 minutes and 3 minutes, respectively, before the second ANP bolus. In the second group, Hoe 140 was given IV, 45 minutes before, and PU-D1 was given ID, 40 minutes before the second ANP bolus. To test for the effect of a local blockade of BK receptors, the third group was given a smaller dose of Hoe 140 (77 pmol, 100 ng) ID 45 minutes before, and PU-D1 10.8 pmol (25 ng) ID 40 minutes before the second ANP bolus.
Durability of the Blocking Effect of PU-D1
To determine the duration of the blockade on ANP-mediated increase of renal excretory function, each rat received 3 ANP boluses at regular intervals of 60 minutes, and 3 minutes before the first bolus, a single dose of 10.8 pmol (25 ng) PU-D1 was given IV. The response of the urinary parameters following each ANP bolus was evaluated. The control group received the same doses of ANP, the first one being preceded by the vehicle of PU-D1.
Additive Effect of Subthreshold Doses of PU-D1 and BK
Three modalities were assayed. (1) In one group of rats, 4.32 pmol (10 ng) of PU-D1 and 47 pmol (50 ng) of BK each dissolved in 50 μL of IGS were injected IV 3 minutes and 1.5 minutes, respectively, prior to the second ANP bolus. (2) In another group, the order of the injections of PU-D1 and BK was reversed. (3) Two mixtures containing different amounts of PU-D1 and BK were tested, each in a different group of rats. One mixture had the same amount of peptides as described above and the other had 2.16 pmol (5 ng) of PU-D1 and 47 pmol (50 ng) of BK. Each mixture was given IV in 50 μL of IGS, 3 minutes before the second ANP bolus.
Statistical Analysis of Data
All values are given as mean±SEM. Excretion of Na and K is expressed in μmol/kg and volume in mL/kg body weight per 20 minutes. MAP is expressed in mm Hg. Statistical significance of the differences between the first and second ANP response was determined for each experimental group by using a paired t test. In addition, to compare the extent of the inhibition induced by different doses of PU-D1, the ANP response ratio, defined as the ratio between the second and first response for each excretory parameter, was calculated. ANP response ratios were submitted to an arcsin transformation and analyzed by unpaired t test using tables for multiple comparisons against a single control (vehicle injection was used as control).
Effects of PU-D1 Administered IV
Table 1⇓ shows the values of Na, K, volume excretion, and MAP in the 20 minutes following the first and the second ANP boluses. In the control rats, the second bolus always produced a larger excretory response in comparison with the first ANP bolus, as described.5 6 Table 1⇓ also illustrates the effect of PU-D1 on the response to the second bolus of ANP. A striking blockade of ANP stimulatory action on the urinary parameters was obtained with PU-D1 at the doses of 10.8 pmol (25 ng) (see Fig 2⇓) and 21.6 pmol (50 ng). Na, K, and volume excretion were decreased by 94%, 47%, and 54%, respectively, after 10.8 pmol PU-D1 and by 70%, 44%, and 37%, respectively, after 21.6 pmol PU-D1. The smaller doses of 2.16 and 4.32 pmol (5 and 10 ng, respectively) and the doses of 43.2 and 108 pmol (100 and 250 ng, respectively) failed to block the response to ANP. With these doses of PU-D1, ANP response ratios did not differ from the control group. In contrast, the largest dose of 216 pmol (500 ng) PU-D1 induced a clear increment in the magnitude of the second ANP response for Na and volume. No significant changes were detected in blood pressure across treatments. A dose of 432 pmol (1 μg) PU-D1 given IV did not modify the systemic blood pressure (not shown).
Effect of PU-D1 Given ID
The effect of PU-D1 given ID 40 minutes before the second ANP bolus is shown in Table 2⇓. In control animals not injected with PU-D1, the second ANP response was moderately but significantly larger than the first response (P<.01 paired t test), similar to that obtained after IV vehicle injections. In general, ID injection of PU-D1 reproduced the blunting actions found by the intravenous route, although the inhibitory effect was less intense (Fig 3⇓) and was maintained through a wider dose range. The doses of 10.8 and 21.6 pmol (25 and 50 ng) inhibited ANP-induced Na excretion by 69% and 44%, respectively, whereas volume excretion dropped by 57% and 32%, respectively. In rats injected with the largest dose of 108 pmol PU-D1 (250 ng), the ANP response ratio for Na and volume was significantly lower than the control, although the second response was not significantly different from the first one. In contrast, the smallest dose of 4.32 pmol (10 ng) PU-D1 induced a significant increase in Na and volume excretion, giving an ANP response ratio significantly larger than that of the control. In general, PU-D1 given either IV or ID inhibits ANP-induced renal excretion, following the already reported pattern described for kinins.6 7
Effect of Hoe 140 on the Anti-ANP Action of PU-D1
The administration of Hoe 140 (1.92 nmol, 2.5 μg) was highly effective for hindering the anti-ANP action of 10.8 pmol (25 ng) PU-D1 given IV or ID. In rats treated with Hoe 140, Na, K, and volume excretion in response to first and second ANP bolus did not differ in spite of PU-D1 IV administration before the second ANP bolus (Fig 2⇑). Similar obliteration of ANP inhibition by PU-D1 was obtained with an IV injection of Hoe 140 5 minutes prior to the administration of 10.8 pmol PU-D1 ID (Fig 3⇑). These findings reproduced the blockade by Hoe 140 of the anti-ANP action of BK and kinins of 15, 16, and 18 amino acids irrespective of the route of administration.5 6 7 8 In another experiment, the introduction of 77 pmol (100 ng) of Hoe 140 in the duodenum, 5 minutes before the injection of 10.8 pmol PU-D1 in the same cavity, also counteracted the blunting effect of this later peptide on ANP excretion. In this group, the urinary parameters following the second ANP bolus were similar to the respective values obtained after the first ANP bolus (+36.6% for Na, +4.0% for K, and +16.7% for volume, n=4).
Durability of the Anti-ANP Effect of PU-D1
A single 10.8-pmol (25 ng) PU-D1 injection inhibited the renal excretory response induced by ANP for a period of 140 minutes (Fig 4⇓). In the control animals, successive injections of 209 pmol (0.5 μg) ANP, given 60 minutes apart, produced similar excretory responses for the three urinary parameters. In PU-D1–treated rats, the ANP responses also were constant over time but were dramatically smaller than controls (P<.001, unpaired t test). In another experiment (not shown) the inhibitory effect was prolonged for more than 3 hours.
Effect of Subthreshold Doses of PU-D1 and BK Given Successively or Simultaneously to Inhibit ANP Renal Excretory Action
Doses of 4.32 pmol (10 ng) PU-D1 (Table 1⇑) or 47 pmol (50 ng) BK were ineffective5 in the inhibition of ANP renal excretory action. However, when the same doses were given successively in the same rat at 3 minutes (PU-D1) and 1.5 minutes (BK) before the second ANP bolus, the diuretic response was blocked, particularly sodium excretion (by 94.4%), as shown in Fig 5⇓. The inhibitory effect was also obtained when the order of the injections was reversed (not shown). However, when the same doses were mixed and injected together, the blockade was not observed (Fig 6⇓). Anti-ANP effectiveness was recovered when the dose of PU-D1 associated with 47 pmol of BK was reduced to 2.16 pmol (5 ng), as can be seen in Fig 6⇓. The three urinary parameters decreased significantly, particularly Na (by 74.3%, P<.01).
The most prominent feature of PU-D1 derived from domain 1 of LMW kininogen by pepsin hydrolysis is its ability to mimic and to reinforce the property of BK to inhibit the diuretic-natriuretic and kaluretic action of ANP (in a narrow dose range). In addition, PU-D1 given as a single small dose of 10.8 pmol completely blocked the ANP-mediated renal excretory action for hours. Intravenously, PU-D1 given alone is 6 to 8 times more active on a molar basis than BK5 and the 15–amino acid kinin PU-15 (met-lys-bradykinin-ser-ser-arg-ile).6 The inhibitory action of PU-D1 on ANP is, like BK or PU-15, completely annulled by the previous administration of the BK B2 receptor blocker Hoe 140. This finding indicates that one of the main effects of PU-D1 is the facilitation of the role of BK as an activator of its B2 receptor. The experiments in which mixtures of PU-D1 and BK were assayed to test the facilitatory action of PU-D1 on BK subthreshold doses reinforce the concept that the amounts required to block ANP effect must reach a critical concentration of both peptides. The occurrence of a kallikrein-kinin system in the kidneys in which BK can function in a paracrine fashion close to glomeruli and tubular regions where B2 receptors of BK stand11 indicates that PU-D1 could play a modulatory role of BK in sodium excretion. We have no explanation yet on how PU-D1 can exert a facilitatory role on BK inhibitory action at the cellular or molecular levels. We are exploring if BK can be protected by PU-D1 from some hydrolytic action of local proteases, allowing intrarenal BK concentration to increase to a critical level to activate B2 kinin receptors. Also, we cannot conclude that PU-D1 may facilitate BK release from kininogen.
Sodium excretion is controlled by several factors that maintain homeostasis and blood pressure level. This is of paramount importance in many physiological and pathological conditions. For this reason we cannot disregard a factor such as PU-D1 that might modify the role of ANP, one of the hormones that participates constantly as a fine regulator of blood volume. It is possible that BK or PU-D1 affects ANP excretory action by modifying the number or activity of ANP clearance receptors, which play a modulatory role in ANP function by decreasing the availability of ANP to stimulate guanylate cyclase receptors.12 The blunted ANP response also may correspond to an increased phosphodiesterase activity in medullary collecting duct cells, leading to a faster cGMP turnover, such as that observed in rats with sodium-retaining disorders.13 We have shown that blockade of ANP excretory response induced by exogenous BK,9 or by inhibition of kininase II,5 is paralleled with a reduced urinary cGMP excretion. In this context, the peculiar finding that ANP inhibition is observed only in a small dose range of either kinins5 6 7 or PU-D1 may be the result of two or more interplaying mechanisms acting independently on ANP clearance and guanylate cyclase receptors, or on intracellular phosphodiesterase activity. Several other possible mechanisms not involving ANP receptors may be considered, like changes in the activity of endogenous proteases, such as the neutral endopeptidase 24.11 enzyme that degrades both kinins and ANP,14 or modifications in prostaglandin E2 production, which inhibits Na reabsorption in renal collecting tubule cells.15 The observation that 216 pmol (500 ng) PU-D1 indeed facilitate rather than inhibit ANP-induced Na and volume excretion closely resembles what is observed with the 15–amino acid kinin PU-15 when injected at doses of 300 to 600 pmol ID or IV.6 These findings suggest that, in addition to the ANP inhibitory effect, PU-D1 shares with kinins the ability to increase diuresis-natriuresis at higher doses; however, this hypothesis requires confirmation.
The multidomain nature of kininogens has been interpreted as a highly refined mechanism for BK release.16 The release of BK by the enzymatic action of kallikreins is the best known function of kininogen domains. Actually, six domains have been described in kininogens and specific activities in a large variety of biochemical processes have been identified for all of them, except for domain 1.17 Domain 2 is multifunctional, capable of inhibiting Ca-activated cysteine proteases, calpain, papain, and cathepsin L, and domain 3 is the most potent inhibitor of cathepsin L and papain.18 In addition, an epitope has been found that inhibits thrombin binding to platelets; domain 4 has the BK sequence; domain 5 binds to surfaces such as endothelium and to a region that binds to Zn and anionic surfaces; domain 6 possesses overlapping sites for kallikrein. Because, to our knowledge, no specific activity has been described for domain 1, it is tempting to speculate that it could be implicated in either a protective antiprotease function to prevent a too-fast BK inactivation, or the inducement of an up-regulation of ANP clearance receptors.12 One of the most provocative questions is whether PU-D1 can be split from its mother molecule, in some physiological or pathological conditions, to exert an anti-ANP action associated or not with BK. We have to take into account that kininogens are part of the kallikrein-kinin system, phylogenetically one of the oldest in living organisms involved in processes such as inflammation, pain, blood coagulation, smooth-muscle contraction and relaxation, vascular endothelial permeability, NO release, blood pressure, and natriuresis. Therefore, we speculate that PU-D1 might share some of the attributes of BK for a fine regulation of diuresis-natriuresis. Another question deals with the physiological events related to blood volume maintenance that might require an inhibition of ANP action on renal excretion. We assume that slowing down the stimulatory effect of ANP on renal excretory functions is a physiological requirement during strenuous muscular exercise, prandial periods,7 and pregnancy.19 The release of ANP from the atria cannot be stopped because ANP participates in the extravascular distribution of fluids during diverse physiological situations.20 During digestion, for instance, a large amount of water and electrolytes is taken from blood plasma by the exocrine glands that produce the digestive juices necessary to maintain the fluidity of the intestinal contents. The remarkable effects of BK (not published), other kinins,6 7 and PU-D1 of inhibiting ANP-mediated diuresis-natriuresis following their introduction in a small dose into the duodenum lends credence to this hypothesis. The kallikrein-kinin system is highly represented in the digestive tract21 and gastric pepsin secretion could release active peptide fragments from kininogens, which could exert a temporal blockade of ANP-stimulated renal excretory functions.
Selected Abbreviations and Acronyms
|ANP||=||atrial natriuretic peptide|
|HMW||=||high molecular weight|
|HPLC||=||high-performance liquid chromatography|
|IGS||=||isotonic glucose solution|
|LMW||=||low molecular weight|
|MAP||=||mean arterial pressure|
|PAGE||=||polyacrylamide gel electrophoresis|
|PU-D1||=||amino acid peptide KYEIKEGDCPVQSGKTWQDC|
We gratefully acknowledge support of this work by grants FONDECYT 662/92 and 1950/990 and by generous financial help from COPEC SA. We also thank José Cornejo and Judith Gengler for their valuable technical assistance and data handling and Dr. Carlos Figueroa of University Austral de Chile for his valuable contribution in the analysis of purified kininogen.
Reprint requests to Dr Héctor R Croxatto, Departamento de Ciencias Fisiologicas, FCCBB, P. Universidad Católica de Chile, Casilla 114-D, Santiago, Chile.
- Received September 17, 1996.
- Revision received October 10, 1996.
- Accepted March 13, 1997.
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