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Query: UMLS:C0011849 (diabetes)
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The relevance of plasma, glandular and renal kallikrein as an intrarenal hemodynamic regulator, in renal hypertrophy, in 1-5 weeks streptozotocin diabetic rats has been investigated. The fasting plasma glandular kallikrein level significantly decreased with increasing duration of diabetes (p less than 0.05). Glandular kallikrein correlated negatively with kidney weight (r = 0.76, p = 0.05). The 24 hour urinary kallikrein excretion significantly increased with increasing duration of diabetes (p less than 0.05), but this level was not correlated with glucose level, nor with kidney weight. Aprotinin (a kallikrein inhibitor) injected (10 X 10(3) KIU/kg) twice daily for 2 weeks in diabetic rats, significantly decreased plasma glucose levels by 28%, 24 hour urinary kallikrein by 37% (p less than 0.05) and kidney weight by 6%. These results suggest that plasma, glandular and renal kallikrein did not play an important role in the renal hypertrophy observed in streptozotocin diabetic rats.
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PMID:Relevance of plasma, glandular and urinary kallikrein in renal hypertrophy in streptozotocin-diabetic rats. 364 9

Very high blood glucose concentrations were seen in rats one day after injection with alloxan or streptozotocin. Those levels fell (compared to day one, p less than 0.005) by the third day after injection and subsequently rose again during the ensuing days. In contrast, no significant differences between treated and control rats in concentrations of submandibular kallikrein were recorded until the tenth day after the initial injection. At that time the submandibular kallikrein concentrations in the alloxanized and streptozotocinized rats were less (p less than 0.01) than those of the untreated rats. A further fall (compared to day ten, p less than 0.005) took place over the next four days. Thus submandibular kallikrein would not seem to have been involved in the early stages of the experimental diabetes. In agreement with that conclusion were the results of a related series of experiments in which exogenous porcine pancreatic kallikrein was administered to alloxanized rats. The kallikrein did not bring about a reduction in the high blood glucose levels.
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PMID:A study of glandular kallikrein in experimental diabetes. 364 33

The renal kallikrein-kinin system is thought to participate in blood pressure regulation and displays abnormalities in human hypertension, as well as in many animal models of hypertension. Urinary excretion and tissue levels of renal kallikrein were measured in streptozocin (STZ)-diabetic rats in relation to blood pressure, glycemia, and insulin treatment. In study 1, STZ-diabetic rats with marked hyperglycemia showed reduced kallikrein-like esterase excretion, compared with control rats, when first measured after 7 days of diabetes (9.9 +/- 2.5 versus 17.5 +/- 2.4 EU/24 h, P less than 0.05). This difference increased with time and, after 210 days, urinary esterase excretion in diabetic and control rats was 6.7 +/- 2.1 and 39.0 +/- 6.0 EU/24 h, respectively (P less than 0.001). Urine kallikrein, measured by radioimmunoassay, was similarly reduced in diabetic rats (40.4 +/- 8.0 versus 88.0 +/- 6.5 micrograms/24 h, at 30 days, P less than 0.001). At 120 days, systolic blood pressures were elevated in diabetic rats (P less than 0.05), and at 180 days over 60% of the diabetic rats had pressures above the highest pressures of control rats. In study 2, STZ-diabetic rats were treated with insulin for 2 wk (2 U NPH at 0800 h, or 2 U NPH at 0800 and 1600 h). In the single-dose group, with hyperglycemia similar to that of diabetic rats in study 1, kallikrein excretion was reduced as early as day 2, compared with nondiabetic rats (56.0 +/- 6.1 versus 109 +/- 9.4 micrograms/24 h, respectively, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 Jan
PMID:Urinary and renal tissue kallikrein in the streptozocin-diabetic rat. 384 6

Based on a study of the kininogenase activity of the total plasma kallikrein in the presence of 3 concentrations of the soybean inhibitor trypsin (0.5, 1.0, 10.0 micrograms/ml) one can measure at a time the activity of tissue kallikrein (without specifying the source) and the activity of 3 forms of plasma kallikrein, including its adsorption on kaolin that characterizes the conformational structure of the enzyme. Examination of 10 healthy subjects and 136 patients revealed a 10 to 20-fold increase in the content of tissue kallikrein in plasma of 70% of diabetes mellitus patients and a 2.5 to 3-fold elevation in 50% of patients with chronic occupational bronchitis, and in 30% of patients suffering from chronic hepatitis. The method suggested makes it possible to have a better insight into the physiological and pathogenetic role of the kinin system and may be used for laboratory control over the treatment efficacy.
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PMID:[Method for determining kallikrein of tissue origin in blood plasma and its clinical significance]. 384 14

To determine if renal functional alterations in diabetes mellitus could be related to disturbances of vasoactive systems, renal plasma flow (RPF), glomerular filtration rate (GFR), PRA (basal and stimulated), plasma catecholamine levels, and urinary excretion of prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, and kallikrein were determined in 21 patients with insulin-dependent diabetes mellitus (IDDM) of short duration and 15 normal subjects. In 7 additional patients with IDDM and in 4 normal subjects, the effect of lysine acetylsalicylate (LAS; 450 mg, iv) on GFR and RPF was studied. Patients with IDDM had higher RPF and GFR than normal subjects. Plasma norepinephrine and basal and stimulated PRA were significantly lower in IDDM than in the control group [161 +/- 82 (+/- SD) vs. 243 +/- 114 pg/ml, 0.19 +/- 0.20 vs. 1.15 +/- 0.33 ng/ml X h, and 0.93 +/- 0.82 vs. 2.8 +/- 1.73 ng/ml X h, respectively). No significant differences were found in the urinary excretion of PGE2, 6-keto-PGF1 alpha, and kallikrein in the two groups. LAS administration significantly reduced RPF (from 641 +/- 72 to 535 +/- 38 ml/min X 1.73 m2) and GFR (from 168 +/- 25 to 150 +/- 18 ml/min X 1.73 m2) in patients with IDDM, but not in normal subjects. In IDDM patients, there was a close direct correlation between the percent decrease in RPF and GFR induced by LAS and the baseline values of these parameters. The results suggest that in IDDM, there may be an imbalance between the degree of activation of the renin-angiotensin and sympathetic nervous systems and the renal production of PGs. The observation that LAS administration reduced RPF and GFR in these patients suggests that renal PGs are involved in the renal hyperperfusion of IDDM.
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PMID:Renal hemodynamic abnormalities in patients with short term insulin-dependent diabetes mellitus: role of renal prostaglandins. 385 81

It has recently been observed that administration of bradykinin to diabetic patients improves peripheral glucose utilization. To verify whether there is an alteration of the kallikrein-kinin system in human diabetes, plasma kallikrein activity was measured in 47 diabetic patients and in 20 control subjects. In diabetics plasma kallikrein activity was significantly higher than in controls: 1.04 +/- 0.04 U/ml (p less than 0.001). Although they do not refute the hypothesis that there is an alteration of the kallikrein-kinin system in diabetes mellitus, these findings do not support such a hypothesis either. Increased synthesis of plasma kallikrein activity may be due to increased synthesis of carbohydrate-protein compounds in diabetes mellitus.
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PMID:Plasma kallikrein activity in human diabetes mellitus. 634 68

It is suggested that the kininogenesis should be assessed from 3 forms of kallikrein which are detected on the basis of their kininogenase activity in whole blood plasma. Heating of blood plasma acidified to pH 3.0 for 15-20 min at 61 degrees C allows for the conditions under which the kallikrein inhibitors (alpha 1-antitrypsin, alpha 2-macroglobulin) are destroyed whereas kallikrein, prekallikrein, low- and high-molecular kininogens (HMK) are preserved, thus constituting a complex of proteins making the kininogenase reaction feasible. Addition of purified preparations of HMK to the neutralized samples of normal and sick individuals' plasma permitted the demonstration that as the kallikrein is raised, the kininogenesis gets actually activated, during which the blood manifests, in the presence of kallikrein hyperactivity, a sufficient amount of HMK. Provided the kallikrein content drops by 50%, the kininogenesis is reduced, which is accounted for by depletion of blood HMK. A 70%- and a greater decrease in the kallikrein content attests to the kininogenesis reduction because of the diminished levels of HMK, prekallikrein and kallikrein. The regularities described have been confirmed by the agreement between the blood plasma kallikrein level and the concentration of blood free kinins revealed during examination of 68 normal individuals and 231 patients suffering from different inflammatory-allergic diseases of the respiratory and hepatobiliary organs, and from diabetes mellitus.
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PMID:[Method of estimating kininogenesis in blood plasma]. 655 1

The renal kallikrein-kinin system is thought to be involved in vasoregulatory and epithelial ion-transporting processes. Renal kallikrein has not been studied in patients with diabetes mellitus, a disease in which abnormalities of renal hemodynamics and electrolyte handling occur. The urinary excretion of this kallikrein was measured in 20 type I diabetic patients and 10 normal subjects. On a 120-meq Na diet, daily kallikrein excretion, determined by both esterase activity and direct RIA, in 12 poorly controlled diabetic patients [hemoglobin A1c (HbA1c) = 14.2 +/- 0.5% (mean +/- SEM)] was significantly greater (P less than 0.05) than excretion in 8 diabetic patients in good to moderately good control (HbA1c = 9.4 +/- 0.5%) or in 10 normal subjects. In these groups, urinary esterase activities were 9.4 +/- 1.0, 6.1 +/- 1.4, and 6.7 +/- 0.5 esterase units/24 h, respectively. Corresponding excretion values of immunoreactive kallikrein were 171 +/- 14, 118 +/- 26, and 123 +/- 11 micrograms/24 h. Creatinine clearances were similar in the three groups. Urinary kallikrein was also measured in 8 diabetic and 8 normal subjects during 7 subsequent days of 10 meq Na intake. It increased less in diabetic patients than in normal subjects during Na depletion (P less than 0.02). The increase in urinary kallikrein in the diabetic patients was inversely related to their HbA1c levels (r = 0.88; P less than 0.01). The effect of glycemic control on urinary kallikrein excretion was determined in nine diabetic patients. Initial glycemic control was achieved using an artificial endocrine pancreas (Biostator) and was maintained by continuous sc insulin infusion with a portable pump. Before glycemic control, urinary kallikrein was 190 +/- 30 micrograms/24 h (by RIA). After 8-12 days of glycemic control, excretion fell to 144 +/- 23 micrograms/24 h (P less than 0.02). The abnormalities in kallikrein excretion in diabetic patients were not correlated with differences in water, electrolyte, protein, glucose, or aldosterone excretion in any of the studies. These results show that kallikrein excretion was increased in patients with poorly controlled insulin-dependent diabetes, and excretion rose less in diabetic subjects with low Na intake than in normal subjects. Strict glycemic control decreased urinary kallikrein excretion. These findings suggest that the renal kallikrein-kinin system is functioning abnormally in diabetes mellitus.
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PMID:Urinary kallikrein excretion in insulin-dependent diabetes mellitus and its relationship to glycemic control. 656 31

The vascular wall itself, through a complex interplay of endocrine, neurocrine and autoparacrine mechanisms, plays an active role in vascular homeostasis. The endothelial cell senses humoral and hemodynamic changes and responds by secreting a variety of metabolically active substances that act locally causing either vasodilatation or vasoconstriction. Kallikrein (KK) and the mRNA for KK are present in arteries and veins. Vascular KK releases kinins from kininogen which circulate in plasma and is also present in vascular tissue. Vascular-derived kinins induce vasodilatation through the release of endothelial compounds (prostacyclin, EDRFs and cytochrome P-450). Disturbance in the delicate balance between vasodilators and vasoconstrictors may play a role in the development of hypertension. Vascular kallikrein (VKK) was significantly (P < 0.05) elevated after 2 weeks of development of renovascular and mineralocorticoid hypertension, and blood pressure was only slightly elevated. However, VKK decreased in both experimental models when blood pressure was increased. It is possible that the increase in VKK in the early stages resulted in increased local vasodilatory activity, thus counteracting the rise in blood pressure. As hypertension developed, KK was significantly decreased in arteries. The decrease in arterial KK during established hypertension is most likely secondary to high blood pressure. When the endothelium is damaged by high blood pressure, diabetes, excessive LDL cholesterol or cigarette smoking, a net imbalance favoring vasoconstriction, proliferation and migration of cells and increased lipid deposition predisposes to specific vascular diseases. Converting enzyme inhibitors (CEI) blunt the proliferative response of vascular smooth muscle cells after endothelial injury. The cardiovascular protective effects of CEI are mediated in part by the antihypertrophic, antihyperplastic and antithrombotic effects of kinins. The vascular kallikrein-kinin system has a promising role in the regulation of vascular homeostasis and some of the CEI effects may be explained by potentiation of the vascular-derived kinins.
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PMID:Vascular-derived kinins and local control of vascular tone. 774 91

1. Diabetes mellitus type I was induced in 3-month old male C57 BL/KS-mdb mice (N = 24) by ip injection of streptozotocin (STZ, 45 mg/kg body weight) for 5 days. 2. To determine the possible protective effects of nitric oxide inhibition against hyperglycemia, the STZ-diabetic rats received two doses of NG-nitro-L-arginine- methyl ester (L-NAME) (10 mg/kg body weight and 10 mg/mouse) dissolved in PBS for 45 consecutive days. Another group of STZ-treated rats was similarly treated with L-arginine (5 mg/mouse). 3. Blood glucose levels were 118 +/- 37 mg/dl after 8 days of L-NAME administration (10 mg/kg body weight, N = 12) and 186 +/- 22 mg/dl (N = 12) after 5 days of L-NAME administration at the 5 mg/mouse dose. Treatment with L-arginine (5 mg/mouse, N = 12) caused a significant increase in blood glucose level to 151 +/- 17.5 mg/dl, showing the relevance of nitric oxide formation in this type of diabetes. 4. In STZ-diabetic mice treated with L-NAME (N = 12), diuresis was reduced by approximately 58% compared to STZ animals, whereas in L-arginine-treated animals (N = 12) diuresis returned to STZ levels. Urinary protein excretion, which was significantly affected by STZ (123% compared to control) was significantly reduced by 66% after treatment with L-NAME for 45 days, whereas treatment with L-arginine caused a return to STZ values. 5. Urinary kallikrein excretion, which was reduced by 80% in STZ mice compared to control, returned to control levels after L-NAME treatment. 6. The present results suggest a relationship between nitric oxide levels and the reduction of diabetic state and improved renal function by L-NAME.
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PMID:Streptozotocin-induced hyperglycemia is decreased by nitric oxide inhibition. 774 93


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