Scientific Contributions

Role of the B2 Receptor of Bradykinin in Insulin Sensitivity

Irena Duka, Sherene Shenouda, Conrado Johns, Ekaterina Kintsurashvili, Irene Gavras, Haralambos Gavras
https://doi.org/10.1161/hy1201.096574
Hypertension. 2001;38:1355-1360
Originally published December 1, 2001

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Abstract

The biological actions of bradykinin (BK) are attributed to its B2 type receptor (B2R), whereas the B1R is constitutively absent, inducible by inflammation and toxins. Previous studies in B2R gene knockout mice showed that the B1R is overexpressed, is further upregulated by hypertensive maneuvers, and assumes some of the hemodynamic functions of the B2R. The current experiments were designed to further clarify the metabolic function of the B2R and to explore whether the upregulated B1R can also assume the metabolic function of the missing B2R. One group of B2R−/− mice (n=9) and one of B2R+/+ controls (n=8) were treated for 3 days with captopril (which produced a similar blood pressure-lowering response in both groups) and studied with the hyperinsulinemic euglycemic clamp. The knockout mice had fasting and steady-state blood glucose levels similar to those of the wild-type mice but a had tendency to higher fasting insulin levels (at 27.8±5.2 versus 18±2.9 mU/L, respectively). However, they had significantly higher steady-state insulin levels (749±127.2 versus 429.1±31.5 mU/L, P<0.05) and a significantly lower glucose uptake rate (31±2.4 versus 41±2.3 mg/kg per minute, P<0.05) and insulin sensitivity index (4.6±0.9 versus 10±0.7 P<0.001). Analysis of B1R and B2R gene expression by reverse transcription-polymerase chain reaction in cardiac muscle, skeletal muscle, and adipose tissues revealed significantly higher B1R mRNA level in the knockouts versus wild-type (P<0.05) at baseline and a further significant upregulation in mRNA by 1.8- to 3.2-fold (P<0.05) after insulin infusion. We conclude that absence of B2R confers a state of insulin resistance because it results in impaired insulin-dependent glucose transport; this is probably a direct B2R effect because, unlike the hemodynamic autacoid-mediated effects, it cannot be assumed by the upregulated B1R.

Bradykinin mediates a variety of biological effects such as vasodilation, vascular permeability, inflammation, pain, and edema.1 It is also known to play an important role in glucose metabolism.2,3 Indeed, it was shown in vitro and in vivo that administration of bradykinin increases the glucose uptake in cultured adipocytes4 as well as in long-term rat experiments5 and in skeletal muscle of human forearm.6 ACE inhibitors were shown to improve glucose utilization,7 an action that is attributed to bradykinin.8,9 In keeping with these data, kininogen-deficient rats were found to be resistant to insulin.10

The effects of bradykinin are mediated by the B1- or B2-type receptor (B1R or B2R). It has been accepted that almost all of the physiologically significant effects of bradykinin, including the metabolic ones, are exerted by activation of the B2R. Indeed, inhibition of the B2R by various antagonists was shown to reverse the amelioration of insulin-dependent glucose transport by ACE inhibitors,11,12 whereas blockade of downstream mediators, such as prostaglandins and NO, had no effect on insulin sensitivity.12 Several studies have shown that the B2R is expressed in tissues dependent on insulin for glucose uptake, such as skeletal muscle and adipocytes.4,13,14 On the contrary, the B1R is not expressed under normal conditions; it has long been known that its expression is induced by toxins or inflammatory mediators and it contributes to endotoxic shock,15 but it has not been associated with metabolic functions.

In a recent series of studies, investigators have used genetically engineered mice with deleted B2R16 to further explore the physiological actions of bradykinin. Using these mice, we observed that the B1R is highly expressed in B2R knockout mice and appears to take over some of the hemodynamic properties of the B2R.17 The present experiments were designed to further explore the metabolic function of the B2R and to investigate whether in the absence of B2R, the upgraded B1R might also be able to take over the metabolic functions of bradykinin. To this aim, we evaluated the differences in insulin sensitivity in B2R knockout mice and their wild-type controls, by using the hyperinsulinemic euglycemic clamp technique.

Methods

Animals

Bradykinin B2R gene knockout mice (B2R−/−)16 and their wild-type B6 129SvF2 controls (B2R+/+), obtained from the Jackson Laboratories (Bar Harbor, Maine), were used in this study. All experiments were conducted in accordance with the guidelines for the Care and Use of Animals approved by the Boston University Medical Center.

Blood Pressure and Heart Rate Monitoring

Systolic blood pressure (SBP) and heart rate were determined with the use of a noninvasive computerized tail-cuff system (BP-2000 Visitech Systems), as described elsewhere.18 After baseline measurements, 2 groups of mice, one B2R−/− (n=9) and one of their wild-type counterparts (n=8), were given 100 mg/kg per day captopril (Sigma Chemical Co) in their drinking water for a period of 3 days.

Euglycemic Hyperinsulinemic Clamp Procedure

Under anesthesia with pentobarbital (50 mg/kg IP), two catheters were inserted in the left jugular vein for infusion of glucose and insulin and one in the iliac artery for blood sampling.12 The mice were maintained supine throughout the 2-hour duration of the procedure on a heating pad at 37°C. Anesthesia was confirmed by the absence of corneal and toe-pinch reflexes. Porcine insulin (Eli Lilly & Co) was infused at a rate 12 mUI/kg per minute, and 5% glucose was infused through a Harvard pump (Harvard Apparatus Inc) at variable rates as needed to maintain euglycemia. Blood samples (10 μL) were collected every 5 to 10 minutes from the iliac artery and assayed by the Accu-ChecII blood glucose monitor; 250 μL of blood was withdrawn to measure plasma insulin levels at time zero and at the end of the hyperinsulinemic infusion. A donor mouse was used to replace the blood withdrawn at the beginning of the experiment. Plasma insulin levels were measured by a rat immunoassay kit (Linco Research).

The following parameters were recorded: (1) fasting plasma glucose and insulin levels, (2) plasma glucose levels at each of the 6 to 8 samplings throughout the clamp period, (3) steady-state plasma glucose levels as reflected by the mean of the plasma glucose levels in the last 30 minutes of the clamp, (4) plasma insulin level at the end of the clamp, and (5) glucose uptake as reflected by the mean glucose amount delivered in the last 30 minutes of the clamp. The insulin sensitivity index was calculated as the ratio of glucose uptake (mg/kg per minute) to steady-state plasma insulin level (mU/L)×102.

Expression of Bradykinin Receptors in Tissues

Total RNA was prepared from heart, skeletal muscle, and adipose tissue, with TRIzol Reagent (GIBCO BRL). A DNase digestion step was performed to increase the purity of the RNA samples with total RNA Isolation Kit S.N.A.P. (Invitrogen). The expression of B1R and B2R in the heart, skeletal muscle, and adipose tissues was examined by reverse transcription-polymerase chain reaction (RT-PCR) techniques as previously described.17

Statistical Analysis

All data are expressed as mean±SEM. Student’s t tests for paired and unpaired data were used as appropriate. The Mann-Whitney rank sum test was used for nonparametric data. Differences at P<0.05 were considered significant.

Results

SBP at baseline and after treatment with captopril are shown in Figure 1. Baseline SBP was higher in knockout mice than in their wild-type controls (121.6±2.94 versus 109.8±1.78 mm Hg, P<0.05). After 3 days of captopril treatment, the SBP decreased significantly in both groups (to 87.5±2.33 mm Hg in the B2R−/− and 91.6±2.41 mm Hg in the wild-type mice), with no difference between the two groups at end point.

Figure1

Figure 1. Tail-cuff blood pressure at baseline and after treatment with captopril for 3 days. Values are expressed as mean±SEM. *P<0.05 between knockout mice and wild-type counterparts. #P<0.001 between baseline and end point (after captopril treatment) for both groups of mice.

The Table shows blood glucose and insulin parameters during the hyperinsulinemic euglycemic clamp procedure. Fasting glucose and insulin were within normal ranges in both groups, (although insulin did tend to be higher in the knockouts), but the knockout mice had higher steady-state insulin levels and lower glucose uptake compared with the wild-type mice. As a result, the insulin sensitivity index was significantly decreased in the B2R gene knockouts.

View this table:
Table 1.

Parameters of Glucose Metabolism in B2R−/− Mice and Wild-Type Counterparts During Hyperinsulinemic Euglycemic Clamp

The B1R and B2R mRNA expression in tissues was determined by means of a semiquantitative RT-PCR assay. The data of B1R mRNA in skeletal muscle at baseline (captopril-treated animals, with no further treatment) and at end point (after hyperinsulinemic euglycemic clamp) are presented in Figure 2A. Insulin infusion induced a 2.3-fold increase of B1R mRNA expression over baseline (P<0.05) in wild-type mice and a further 1.9-fold (P<0.05) increment in the knockout mice, in which the B1R was already overexpressed at baseline. The level of B1R mRNA expression was significantly higher (P<0.05) in the B2R−/− mice compared with the B2R+/+ at both baseline and end point. The B2R mRNA levels in skeletal muscle are shown in Figure 2B. Insulin infusion induced a 1.8-fold increase over baseline (P<0.05) in B2R expression in wild-type mice. As expected, there was no B2R mRNA in the knockout mice.

Figure2

Figure 2. Analysis of B1R mRNA (A) and B2R mRNA (B) in skeletal muscle at baseline (captopril treated) and end point (captopril treated, after hyperinsulinemic euglycemic clamp) in B2R−/− and B2R+/+ mice. Top, Representative RT-PCR; bottom, mean densitometric data expressed as ratio of 18S mRNA (n=3 in each group). *P<0.05 between knockout and wild-type mice, #P<0.05 between baseline and end point.

Figure 3 shows the B1R mRNA expression (panel A) and B2R expression (panel B) in adipose tissue at baseline and end point. The B1R expression was upregulated 1.6-fold over baseline (P<0.05) in both knockout and wild-type mice. Figure 3B shows a 3.2-fold increase in B2R expression over baseline (P<0.05) in the wild-type mice submitted to hyperinsulinemic euglycemic clamp.

Figure3

Figure 3. Analysis of B1R mRNA (A) and B2R mRNA (B) in adipose tissue at baseline (captopril treated) and end point (captopril treated, after hyperinsulinemic euglycemic clamp) B2R−/− and B2R+/+ mice. Top, Representative RT-PCR; bottom, mean densitometric data expressed as a ratio of 18S mRNA (n=3 in each group). #P<0.05 between baseline and end point.

The data of BR mRNA expression in heart are presented in Figure 4. Panel A shows that B1R is already overexpressed in the knockouts at baseline and is further upregulated in both knockout and wild-type mice after insulin infusion by 1.6- and 1.9-fold over baseline, respectively (P<0.05). Figure 4B shows that the procedure induced a 2.8-fold (P<0.05) increase in B2R expression over the control level in wild-type mice.

Figure4

Figure 4. Analysis of B1R mRNA (A) and B2R mRNA (B) in heart tissue at baseline (captopril treated) after and end point (captopril treated, after hyperinsulinemic euglycemic clamp) in B2R−/− and B2R+/+ mice. Top, Representative RT-PCR; bottom, mean densitometric data expressed as ratio of 18S mRNA (n=3 in each group). #P<0.05 between baseline and end point.

Discussion

This study used the hyperinsulinemic euglycemic clamp technique to evaluate the impact of the absence of the B2R on insulin-dependent glucose transport. Although studies without ACE inhibition would better reflect physiological conditions, we chose to use pretreatment with ACE inhibition to maximize the influence of endogenous bradykinin. We found that animals lacking the B2R had a similar BP response to the ACE inhibitor as the wild-type animals but exhibited relative insulin resistance, as shown by tendency to elevated fasting insulin levels that were further exaggerated during hyperinsulinemic conditions under ACE inhibition. Although elevated insulin levels could be attributable to reduced insulin clearance, their presence in the face of normoglycemia is characteristic of diminished tissue sensitivity to insulin. Glucose uptake was reduced by 25% and the insulin sensitivity index by 54% compared with the wild-type mice. The data indicate that absence of B2R causes a state of insulin resistance, as it is associated with impaired glucose metabolism. This is in agreement with previous data, which have shown that selective antagonists of the B2R decrease glucose uptake and insulin sensitivity and abolish the improvement in insulin sensitivity produced by ACE inhibitors.9,11,12

The contribution of bradykinin to glucose metabolism was suggested years ago, when in vitro and in vivo studies demonstrated that exogenous administration of bradykinin improved insulin sensitivity.19,20 It has been shown that bradykinin enhances insulin receptor phosphorylation and insulin-stimulated translocation of GLUT4 from cytosol to plasma membrane.4,21 A recent study in 32D cells demonstrated that bradykinin enhances the activity of the insulin receptor and downstream insulin signaling cascade through the B2R-mediated signal pathway.22 Inhibition of the ACE, which is identical to the kininase II that mediates degradation of kinins,23 results in potentiation of bradykinin effects. It is therefore not surprising that the state of insulin resistance that typically accompanies essential hypertension24 was shown to be improved by treatment with ACE inhibitors.7,11,25,26

The exact mechanisms of this effect remain controversial. Improved capillary blood flow27 may contribute to it but is clearly not the main mechanism, because other vasodilators have no such properties. In previous studies12 we demonstrated that this is a direct effect of the B2R on insulin-dependent glucose transport because it is not mediated by downstream autacoids; indeed it could be abolished by selective B2R antagonists but not by the prostaglandin inhibitor indomethacin or the NO synthase inhibitor nitro-l-arginine methyl ester (L-NAME). Although other investigators have corroborated these findings,28 there is still no unanimous agreement as to the role of local tissue mediators in this aspect of the B2R function.9,29 Nevertheless, it is possible that alterations in number or function of B2R may contribute to the diminished insulin sensitivity encountered in conditions, such as normal aging or essential hypertension.

In a recent study, we found that the B1R, which is physiologically inert, was actually overexpressed in B2R knockout mice at baseline and was further upregulated during hypertensive procedures.17 Furthermore, under those conditions it appeared to take over part of the hemodynamic effect of the missing B2R. This would explain why the B2R knockout mice have no lesser antihypertensive response to ACE inhibition than the wild-type, as described several years ago.30 These findings are consistent with the BP results of the current study, in which the BP response to ACE inhibition remained unaffected. The cardiovascular phenotype of B2R knockout mice is a matter of controversy in the literature, as some authors have found them to be normotensive at baseline31 whereas others have found them to be hypertensive,32 which is in agreement with our own current and previous17 data. These discrepancies are difficult to explain because they may reflect not only the genetically engineered mutation but also selection, genetic drift, and epistatic interactions that may occur in small-size colonies.33

Regardless of cardiovascular phenotype, the current study was designed to further clarify the metabolic role of the B2R and to explore whether the upregulated B1R may also be capable of taking over part of the metabolic properties of bradykinin. Additional studies using specific B1R antagonists would, of course, further corroborate or refute these data, because it is possible that resistance to insulin might become further accentuated during B1R blockade. Nevertheless, the increased insulin resistance in the B2R−/− mice suggests that the upregulated B1R receptor does not take over the metabolic function of the missing B2R. This evidence may also be taken to further support the notion that unlike the hemodynamic action, the metabolic action is a direct effect of the B2R, not mediated by downstream autacoids such as NO or prostaglandins, which may respond to stimulation by other receptors. One could offer possible speculative explanations for the failure of the B1R to exert direct effects, for example, failure to internalize.

In wild-type mice, analysis of the mRNA expression of the B1R and B2R in skeletal muscle, heart, and adipose tissues, that is, tissues that are most dependent on insulin for glucose uptake, revealed that the insulin infusion induced also an upregulation of B2R. This receptor is constitutively present, and its upregulation by this maneuver is a novel finding. This is consistent with the notion that this bradykinin receptor plays an important role in insulin-mediated glucose transport in skeletal muscle, adipose tissue, and heart, although differences in degree of overexpression among tissues are difficult to explain. An unexpected finding, however, was that along with the B2R upregulation, there was also in these animals an increase in B1R gene expression, although to a much lesser extent than the B2R and to degrees varying widely among different tissues. As mentioned earlier, it is known that the B1R is not expressed under physiological conditions, but pathological conditions such as inflammation and tissue damage induce its expression in vascular and nonvascular tissues.15 The inducibility of this receptor was first described in isolated rabbit aorta, in which a time-dependent and protein synthesis-dependent contractile response to des-Arg-BK was observed.34,35 It was recently shown that the BK B1R upregulation involves activation of protein kinases through participation of nuclear factor-κB, identified in the promoter region of the B1R gene.36–38 Insulin receptor activation also involves mobilization of tyrosine kinase,39 similar to the mobilization induced by cytokines, which may explain the inducibility of B1R by insulin. The functional significance, if any, of this phenomenon, remains unclear at this time. Usually, biologic responses have a teleologically plausible, even if speculative, justification. Accordingly, it is easy to explain why deletion of B2R would elicit induction of B1R, which is also capable of stimulating release of local tissue mediators such as NO and prostaglandins40 and hence maintain local tissue perfusion. Likewise, it is easy to see why infusion of insulin and glucose would upgrade expression of the B2R; however, a change in transcriptional regulation of the B1R gene by this maneuver, especially in the presence of a normally functioning upgraded B2R, is difficult to explain away when the B1R can have no impact on glucose metabolism. Of course, it should also be kept in mind that increased B1R mRNA does not necessarily imply increased generation of B1R protein, although it is strongly suggestive.

Other pathological conditions, in which upregulation of the B1R has been described in various tissues, include regional ischemia41 and hyperglycemia caused by diabetes mellitus induced by streptozotocin.42,43 All of these experiments, however, have only explored the hemodynamic functions assumed by the B1R, which become activated even in the presence of functional B2R and contribute to the tissue-protective effects of BK through enhanced release of local vasoactive mediators. Besides, streptozotocin diabetes is akin to type 1 (insulin-deficient) diabetes and therefore would not be a suitable model for assessing the metabolic role of BK receptors on the insulin-resistance characteristic of type 2 diabetes.

In summary, the present data confirm and amplify our previous finding that the absence of a functional B2R induces overexpression of the B1R in a variety of tissues. They further confirm previous reports by us and others that the metabolic function of bradykinin, that is, enhanced insulin-dependent glucose transport, is a function of the B2R because its absence causes a state of considerable insulin resistance; they also suggest that this metabolic effect probably is exerted directly, for example, without mediation by local autacoids. Unlike the hemodynamic effects of bradykinin, which, in the absence of B2R can be assumed by the upgraded B1R, the metabolic effects of bradykinin appear to be exerted exclusively through the B2R.

Acknowledgments

This study was supported in part by National Institutes of Health grants R01-HL-58807 and P50-HL-55011.

Footnotes

  • Dr Duka and Dr Shenouda contributed equally to this work.

  • Received April 5, 2001.
  • Revision received April 27, 2001.
  • Accepted June 29, 2001.

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  • Role of the B2 Receptor of Bradykinin in Insulin Sensitivity
    Irena Duka, Sherene Shenouda, Conrado Johns, Ekaterina Kintsurashvili, Irene Gavras and Haralambos Gavras
    Hypertension. 2001;38:1355-1360, originally published December 1, 2001
    https://doi.org/10.1161/hy1201.096574
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