Plasma Prekallikrein

Abstract

The relevance and significance of the plasma kallikrein/ kinin system as a risk factor for the development of vascular complications in diabetic patients was explored in a cross-sectional study. We measured the circulating levels of plasma prekallikrein (PK) activity, factor XII, and high؊molecular weight kininogen in the plasma of 636 type 1 diabetic patients from the Diabetes Control and Complications Trial/Epidemiology and Diabetes Intervention and Complications Study cohort. The findings demonstrated that type 1 diabetic patients with blood pressure >140/90 mmHg have increased PK levels compared with type 1 diabetic patients with blood pressure <140/90 (1.53 ؎ 0.07 vs. 1.27 ؎ 0.02 units/ml; P < 0.0001). Regression analysis also determined that plasma PK levels positively and significantly correlated with diastolic (DBP) and systolic blood pressures (SBP) as continuous variables (r ‫؍‬ 0.17 and 0.18, respectively; P < 0.0001). In multivariate regression analysis, the semipartial r 2 value for PK was 2.93% for SBP and 2.92% for DBP (P < 0.0001). A positive correlation between plasma PK levels and the urinary albumin excretion rate (AER) was also observed (r ‫؍‬ 0.16, P < 0.0001). In categorical analysis, patients with macroalbuminuria had a significantly higher level of plasma PK than normoalbuminuric patients (1.45 ؎ 0.08 vs. 1.27 ؎ 0.02 units/ml; P < 0.01), whereas microalbuminuric patients had an intermediate PK value (1.38 ؎ 0.05 units/ml; P ‫؍‬ NS). Among patients in the microalbuminuric subgroup, we observed a positive and independent correlation between PK and AER in univariate and multivariate regression analysis (r ‫؍‬ 0.27, P < 0.03; n ‫؍‬ 63). We concluded that in type 1 diabetes, 1) PK levels are elevated in association with increased blood pressure;2) PK levels are independently correlated with AER and are categorically elevated in patients with macroalbuminuria; and 3) although the positive correlation between PK and AER within the subgroups of patients with microalbuminuria suggest that PK could be a marker for progressive nephropathy, longitudinal studies will be necessary to address this issue.

The Role of Bradykinin System in Type 2 Diabetes

“…This may also suggest that high levels of tissue kallikrein in diabetic patients might be a predisposing factor in the induction of type 2 diabetes due to the inhibition of glucose transfer to the tissues [38]. Plasma levels of tissue kallikrein have been reported to be increased in type 2 diabetes as previously reported [39,40]. In the present study however, we also observed high concentrations of plasma tissue kallikrein, which presumably be due to the hyperactivity of the BK-forming system to induce systemic metabolic abnormalities.…”

Bradykinin System and Type 2 Diabetes

“…Acute administration of aprotinin, a kallikrein inhibitor, and/or B2R antagonist in these hyper filtering diabetic rats reduced the GFR and RPF [11,12] These findings may suggest that the high levels of renal tissue kallikrein and BK may mediate renal hyper filtration in diabetes. There was no alteration in the creatinine levels in the present study; however, high plasma prekallikrein levels may suggest the onset of renal abnormalities .In fact, high plasma prekallikrein levels have been documented in type 1 diabetic patients [10]. These investigators suggested that increased plasma prekallikrein level could be a risk factor for hypertension and nephropathy in type 1 diabetes.…”

“…BK is rapidly (< 15 sec) inactivated by circulating kinases [9]. BK acts on B1receptor (B1R) and B2 receptor (B2R) [10] to elicit physiological and pharmacological actions. It has been shown previously that type 1 diabetic patients are at a risk of developing nephropathy, having increased renal tissue kallikrein and BK levels [11].…”

Plasma Kallikrein Promotes Epidermal Growth Factor Receptor Transactivation and Signaling in Vascular Smooth Muscle through Direct Activation of Protease-activated Receptors

“…The principal effectors of the two systems, angiotensin II and BK, exert opposing effects on vascular tone, with angiotensin II directly promoting VSMC contraction and BK indirectly causing vasodilation through BK receptor-mediated NO generation by vascular endothelial cells. Despite the generally salutary effects of BK, it is clear that dysregulation of the KKS is associated with progression of the vascular and renal complications of diabetes mellitus (40). In the setting of endothelial denudation, BK can act directly on B1 and B2 bradykinin receptors expressed by VSMC to promote vasoconstriction in a manner similar to angiotensin II (13).…”