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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mesangial cell is a contractile secreting cell found in a key position in the renal glomerulus. Several kidney and systemic diseases are associated with dysfunctions of the mesangial cells. We compared the effect of bradykinin (BK; B2 agonist) and des-Arg9-bradykinin (DBK; B1 agonist) on intracellular calcium mobilization, cell proliferation, and collagen secretion of mesangial cells from normal and streptozotocin-induced diabetic rats. Stimulation of mesangial cells with BK and DBK caused an increase in intracellular calcium (Ca2+). However, the patterns of the Ca2+ increases induced by BK and DBK were different, indicating that DBK induced a major Ca2+ influx, whereas BK preferentially released Ca2+ from intracellular pools. Stimulation with BK and DBK did not show any heterologous desensitization, thus indicating the presence of two distinct binding sites. In normal cells, DBK stimulated cell proliferation more than BK, and this action was potentiated by insulin. No effect of BK or DBK was found in cells harvested from diabetic rats. The proliferation effect of BK and DBK was restored by insulin. DBK stimulated more collagen synthesis than BK in normal cells. In cells harvested from diabetic rats the collagen secretion was increased, but BK and DBK no longer had any effect. Insulin reduced basal collagen secretion in normal cells and cells harvested from diabetic rats. Insulin also blunted stimulation by BK and DBK in normal cells but did not restore the response to BK and DBK in cells harvested from diabetic rats. Our results show that the sensitivity to DBK and BK decreases during the course of insulin-dependent diabetes, indicating modulation by insulin.
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PMID:Comparison of B1 and B2 receptor activation on intracellular calcium, cell proliferation, and extracellular collagen secretion in mesangial cells from normal and diabetic rats. 884 20

The renal kallikrein-kinin system (KKS) was studied in pair-fed streptozotocin (STZ)-induced diabetic rats and compared with age-matched controls. Twelve weeks after STZ injection, rats were normotensive, showed hyperglycemia, proteinuria, polydipsia and reduced glomerular filtration rate (GFR) and body weight. The activities of urinary prekallikrein (PKLK) and kallikrein (KLK) were reduced accompanied by an up to 3-fold increase of bradykinin (BK) excretion compared to controls. The increased BK excretion suggests that the renal KKS in STZ-diabetes is activated and that the reduction in urinary PKLK and KLK activity may be due to an increased consumption of these enzymes or to a negative feedback mechanism. The stimulation of the renal KKS in STZ-diabetes could reflect an attempt of the organism to balance glomerular hypertension.
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PMID:Bradykinin excretion is increased in severely hyperglycemic streptozotocin-diabetic rats. 885 82

In healthy, fasted volunteers, the ingestion of a test meal produced within 30 min, a decrease of ca. 40% of high molecular weight kininogen (HK) in plasma. Return to control (fasting) levels occurred after 90-120 min. Low molecular weight kininogen (LK) remained unchanged or was slightly elevated. On another occasion, the same group of fasted volunteers received an intravenous, euglycemic-clamped infusion of insulin. This treatment reproduced the effects of the test meal on HK. Insulin had no effect on kininogen following incubation with plasma or whole blood. Slight systemic hypotension and increased leg muscle blood flow accompanied postprandial plasma kininogen change. It is suggested that such vascular changes may in part, be due to bradykinin (BK) released from HK cleaved at vascular, possibly endothelial sites activated by insulin following its release by alimentary stimulation. A decreased capacity to release BK due to absence of, or lowered sensitivity to, insulin may play a role in the origin of hypertension in diabetes.
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PMID:Kininogen changes in human plasma following a test meal or insulin administration. 885 85

Streptozotocin (STZ) has been extensively used to produce type I diabetes in animals. This experimental disease is characterized by a mild inflammatory reaction in the Langerhans islets. Because kinins have been proposed as prominent inflammatory mediators in the pathogenesis of several diseases, we decided to evaluate the role of kinins and their receptors in the evolution of insulitis. Male C57BL/Ks mdb mice were injected with STZ (40 mg/kg) for 5 consecutive days. The kinin B1 receptor antagonist [Leu8]des-Arg9-bradykinin or the B2 antagonist d-Arg[Hyp3,Thi5,D-Tic7, Oic8]bradykinin (HOE-140) was injected subcutaneously into STZ mice at 300 micrograms/kg body weight twice a day and 500 micrograms/kg per day, respectively. Treatment with antagonists was started 3 days after STZ and lasted for 10 days. Plasma glucose was determined by the glucose oxidase method, and urine samples collected on day 13 were assayed for proteins, nitrites, and kallikreins. Diabetic mice showed hyperglycemia and increased diuresis, marked proteinuria, and increased excretion of nitrites and kallikreins. The treatment with the B2 receptor antagonist did not show any effect on glycemia, but it significantly reduced water and protein excretion, compared with the STZ group. STZ mice treated with the B1 receptor antagonist showed normal glycemia and complete normalization of diuresis and protein, nitrite, and kallikrein excretion. The results obtained in the present investigation support the assumption that the kallikrein-kinin system intervenes in the maintenance of diabetic lesions, and they also indicate that B1 kinin receptors play a significant role in this experimental disease.
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PMID:Effects of B1 and B2 kinin receptor antagonists in diabetic mice. 888 24

1. This study was designed to investigate the influence of insulin treatment and islet transplantation on the smooth muscle contractility and endothelium-dependent and independent relaxation of resistance arteries in the chemically induced streptozotocin (STZ) diabetic rat after 6-8 weeks, and 12-14 weeks of diabetes, compared to non-diabetic age-matched controls. 2. The morphology, and contractile responses to high potassium physiological salt solution (KPSS), KPSS containing 10(-5) M noradrenaline (NAK), and concentration-response curves to noradrenaline (NA) of mesenteric resistance arteries were recorded, along with the endothelium-dependent relaxation responses to acetylcholine (ACh) and bradykinin (BK), and endothelium-independent relaxation to sodium nitroprusside (SNP). Concentration-response curves were then repeated in the presence of a nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NOARG). 3. Insulin-treated diabetic rats in the 12 week study demonstrated enhanced vascular contractility to KPSS, NAK and NA, compared to age-matched non-diabetic controls. 4. Incubation with L-NOARG resulted in both a significant increase in maximum contractile response, and sensitivity (pD2) to NA in the untreated diabetic group (6 weeks). A significant shift in sensitivity was also seen in the insulin-treated diabetic group. In the 12 week study, incubation with L-NOARG resulted in an increased maximum contractile response and sensitivity to NA in the insulin-treated diabetics. An increase in sensitivity was also observed in the untreated diabetic group. 5. Endothelium-dependent relaxation to ACh was significantly augmented in the untreated diabetics (6-weeks), compared to the control group. In the 12-week study, relaxation to both ACh and BK was not significantly different in any of the experimental groups when compared to the sham-operated non-diabetic controls. 6. Incubation with L-NOARG resulted in a significant attenuation of the maximum relaxation response to ACh and BK in all of the experimental groups, in the 6- and the 12-week study. 7. There was no significant difference in the maximum relaxation response or sensitivity to sodium nitroprusside between the diabetic groups and their age-matched controls in either the 6-week or the 12-week study. 8. The results of this study suggest an enhanced release of nitric oxide in the early stages of diabetes, which is more evident in the untreated diabetic rats than the insulin treated, and appears to normalize as the duration of diabetes progresses. This study also shows that the alteration in vascular reactivity of the resistance arteries can be restored to within normal limits by the transplantation of islets of Langerhans, and that islet transplantation is an effective strategy in the correction of the metabolic abnormalities associated with insulin-dependent diabetes.
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PMID:The effect of insulin treatment and of islet transplantation on the resistance artery function in the STZ-induced diabetic rat. 889 69

In this review paper, three aspects related to alteration in capillary permeability, based on a series of recent observations from this laboratory, are examined. Firstly, the determinants of capillary extravasation, which include pre- and post-capillary resistances in different microcirculation networks, as well as endothelial permeability per se, are described with particular reference to the heterogeneous character of both regulatory components, reported by this and other groups. Secondly, the endothelium-interstitium relationship, responsible in part for the maintenance of the interstitial compartment physicochemical characteristics, is introduced as an important factor in regulating the traffic of vital nutrients delivered to the cell mass, and the removal of waste products from the cellular compartment to the microcirculation, for ultimate excretion. Examined in this manner, it appears that modulation of capillary permeability is essential for the maintenance of cellular life, yet the neurohumoral mechanisms involved in the control of microcirculation networks are just starting to be identified. A number of morbid conditions characterized by multiorgan involvement exhibit a common pathophysiological denominator which involves endothelium-interstitium relationships, as illustrated in experimental animal models of arterial hypertension, diabetes mellitus, heart failure, and degenerative renal diseases. Enhanced capillary permeability associated with local interstitial edema in specific organs, such as the heart and the kidney, in arterial hypertension and diabetes mellitus, as well as decreased permeability in peripheral tissues, such as the skeletal muscle and the skin, in congenital cardiomyopathy, have been documented. It is likely that alteration in the characteristics of interstitial matrix composition contributes to target organ damage in these examples of systemic disorders from different etiologies. Thirdly, the recent identification of autocoids and hormones involved in the direct and indirect control of capillary permeability has led to the development of pharmacological tools capable of modulating pre- and post-capillary vascular tonus, as well as endothelial permeability. Angiotensin II antagonism, bradykinin B1-receptor inhibition, and modulation of eicosanoid production, in particular thromboxane A2, are associated in some of the above-described disorders, with normalization of capillary permeability defects, and occasionally with improvement in organ function. The eventual development of agents capable of directly controlling the physicochemical characteristics of the interstitial matrix should be of interest, not only for preventing the development of irreversible matrix structural alterations but also for facilitating the traffic of metabolites between capillaries and the cell mass of vital organs.
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PMID:Consequences of alteration in capillary permeability. 894 69

To evaluate the effect of angiotensin-converting enzyme inhibition on spontaneous and insulin-stimulated endothelin-1 (ET-1) secretion in vitro and in vivo, human endothelial cells derived from umbilical cord veins were cultured onto acellular collagen-coated permeable membrane, thus mimicking in vivo conditions with a luminal and abluminal side. Insulin (10(-6,-8,-9) mol/l) significantly stimulated ET-1 secretion by cultured cells (P < 0.05 starting from 2-h incubation). Captopril (10(-7,-8,-9) mol/l) significantly reduced both spontaneous and insulin-stimulated ET-1 secretion, while increasing nitric oxide production. Considering each cell side, captopril significantly inhibited the apical secretion of ET-1, while its effect on the basolateral compartment was modest. In the presence of D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin (10(-6) mol/l), a bradykinin B2 receptor antagonist, captopril had no effects on ET-1 and nitric oxide production and also when insulin was added to the culture media. With regard to in vivo experiments, oral captopril therapy (25 mg twice daily for 1 week) was given to normotensive (n = 5) and hypertensive (n = 6) subjects and significantly decreased plasma ET-1 concentration (normotensive subjects, before: 0.98 +/- 0.09 pg/ml; after: 0.55 +/- 0.08 pg/ml, P < 0.0001; hypertensive subjects, before: 1.05 +/- 0.03 pg/ml; after: 0.56 +/- 0.05 pg/ml, P < 0.0001). Transient hyperinsulinemia was accompanied by a significant rise in plasma ET-1 concentrations in both groups (P < 0.0001 at 180 and 210 min) before but not after captopril treatment. In conclusion, captopril inhibits both spontaneous and insulin-stimulated ET-1 secretion by endothelial cells, acting on angiotensin-converting enzyme bound to the luminal cell side. In vivo, captopril significantly reduces plasma ET-1 levels in both basal and insulin-stimulated conditions.
Diabetes 1997 Jan
PMID:Effects of ACE inhibition on spontaneous and insulin-stimulated endothelin-1 secretion: in vitro and in vivo studies. 897 Oct 86

The kallikrein-kinin system (KKS) has been postulated to play a role in modulation of hemodynamic function in diabetes and to contribute to the hemodynamic effects of angiotensin-converting enzyme inhibition (CEI). To further explore the KKS and its interactions with the renin-angiotensin system (RAS), studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic rats. In protocol 1, control and diabetic rats were studied before and after administration of one of two dissimilar B2 kinin receptor antagonists (BK2As), or vehicle. At a low dose (0.5 microg x kg-1 x min-1), the first generation antagonist D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin significantly reduced the glomerular filtration rate (GFR) and renal plasma flow rate in diabetic rats, despite variable effectiveness in blocking the hypotensive response to injected bradykinin. However, a similar hemodynamic effect occurred in nondiabetic rats, suggesting that the observed effect was not specific to diabetes. Higher doses (20 microg bolus, then 1 microg x kg-1 x min-1 infusion) did not affect hemodynamics in either group, perhaps because of partial agonist effect. The second BK2A tested was the newer compound, icatibant (Hoe 140; D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). Hoe 140 consistently blocked the vasodepressor action of injected bradykinin, but had no effect on systemic or renal hemodynamics in either control or diabetic rats. In protocol 2, control and diabetic rats were pretreated with the CEI ramipril for 1-2 weeks, after which renal function was studied before and after Hoe 140 (0.1 mg s.c. and i.v.) or vehicle. CEI lowered blood pressure in both groups. Hoe 140 did not affect renal function in control rats, but in diabetic rats pretreated with ramipril, it induced a modest but significant decline in GFR. Ramipril induced the predicted changes in the systemic and intrarenal RAS, while acute BK2A had no consistent effect on RAS parameters. These studies suggest that the endogenous KKS has only a minor role in modulation of renal hemodynamics in the euvolemic diabetic rat, in the absence of KKS stimulation by CEI. However, angiotensin-converting enzyme is also kininase II, which serves to increase endogenous kinin activity. The increased kinin activity resulting from CEI treatment may participate, to a modest degree, in hemodynamic regulation of the diabetic kidney.
Diabetes 1997 Jan
PMID:Interactions of the kallikrein-kinin and renin-angiotensin systems in experimental diabetes. 897 Oct 89

There has been a prejudice that diabetes modulates the function of saphenous vein in a manner that predisposes to bypass graft failure, although most of the evidence accrues from animal studies. We have investigated the effect of diabetes on the vasodilator responses and ultrastructure of saphenous vein harvested from patients undergoing infrainguinal bypass surgery for limb salvage and the development of stenoses within the vein grafts. Of 55 consecutive patients undergoing vein bypass surgery for critical ischemia, 16 (29%) were diabetic: diabetes was not a risk factor for graft stenosis, which occurred in 17 of 56 (30%) grafts. Endothelium-dependent relaxation by nitric oxide pathways stimulated after receptor activation (bradykinin and thrombin) was not different in vein rings from diabetic (n = 12) and nondiabetic patients (n = 12). Prostarioid-mediated vasorelaxation was absent in vein rings from diabetic patients, and the production of 6-keto prostaglandin F(1alpha) (PGF(1alpha)) from diabetic vein was only 66 +/- 27 pg x cm-2 x min-1 compared with 112 +/- 20 pg x cm-2 x min-1 from control vein (P = 0.011). Fibrinogen-mediated vasorelaxation, normally inhibited by K+ channel blockers, was negligible in vein from diabetic patients. No ultrastructural differences were observed between the endothelium of saphenous vein harvested from diabetic and nondiabetic patients. However, diabetes was associated significantly with the presence of spiraled collagen in media. The maintenance of receptor-activated stimulation of nitric oxide pathways and the damping of the response to fibrinogen in saphenous vein endothelium may provide, in part, for the good prognosis of vein graft surgery in diabetic patients: diabetes is not a risk factor for early (12 months) infrainguinal vein graft stenosis.
Diabetes 1997 Jan
PMID:The influence of diabetes on the vasomotor responses of saphenous vein and the development of infra-inguinal vein graft stenosis. 897 Oct 90

Tissue kallikrein is a serine proteinase which processes kininogens to release bioactive kinins. Kinins mediate a variety of biological processes through the interaction with kinin receptors. Kinins are involved in the regulation of blood pressure and local blood flow, vasodilation, smooth muscle contraction and relaxation, production of pain and inflammation, and stimulation of cell proliferation. The tissue kallikrein-kinin system has been implicated in a number of pathophysiological processes such as hypertension, allergy and diabetes mellitus. In the present study, we have identified the expression and localization of components of the kallikrein-kinin system in the human eye by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analyses, and in situ hybridization histochemistry. RT-PCR and Southern blot analyses have detected mRNAs of the key components of the system including tissue kallikrein, low molecular weight kininogen, and bradykinin B1 and B2 receptors at high levels in human retina, choroid and ciliary body, and relatively low levels in the optic nerve. In situ hybridization has identified cellular localization of these four mRNAs in ocular tissues. They are expressed in retinal neuronal cells including the outer nuclear layer, inner nuclear layer and ganglion cell layer. These mRNAs were also identified in endothelial cells of ocular blood vessels, ciliary muscle and lens epithelial cells. The sense riboprobes showed negative staining, which indicates the specificity of the antisense riboprobes. These results suggest that the tissue kallikrein-kinin system is produced endogenously in human ocular tissues. Similar expression patterns of kallikrein, kininogen and kinin receptors indicate that the kallikrein-kinin system may function in an autocrine or paracrine fashion in the eye.
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PMID:Expression and cellular localization of the kallikrein-kinin system in human ocular tissues. 898 60


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