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

To investigate in mice the mechanisms underlying renal functions in a type I diabetes model, we have suppressed B2 kinin receptors local activities by their specific antagonist D-Arg [Hyp3-Thi5-D-Tic7-Oic8]BK (HOE 140). Mice made diabetic with low consecutive doses of streptozotocin (STZ) (45 mg/k BW during 5 days) were injected with HOE 140 (15 micrograms/twice a day) for 15 days. This drug did not modify glycemia of STZ treated animals but a significantly reduction of urinary proteins, nitrites and kallikrein was observed. These results indicate that kinin B2-receptors activation is implicated in the alterations of renal function in this model of type I diabetes in mice.
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PMID:Effects of HOE 140 on some renal functions in type I diabetic mice. 881 12

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

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

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

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

The factors that initiate chronic renal failure in patients with hypertension, diabetes mellitus, and chronic glomerular disease are largely unknown. The likely genetic contribution to ESRD, particularly in African Americans, suggests that linkage analysis may be useful to evaluate the role of candidate genes in the pathogenesis of chronic renal failure. The renin-angiotensin-aldosterone (RAA) axis has been intensively evaluated for its contribution to cardiovascular disease and nephropathy. This study tested for linkage between candidate genes in the RAA axis and chronic renal failure, using 85 African-American sibling pairs (from 65 families) concordant for ESRD. Angiotensinogen was selected because of the putative link between it and mild to moderate essential hypertension and nephrosclerosis; angiotensin-converting enzyme because of its possible contribution to diabetic nephropathy; and renin, the angiotensin II receptor, and kallikrein because of their roles in hypertension and renal perfusion. These candidate loci did not demonstrate linkage to either diabetic or nondiabetic renal disease in this study's collection of sibling pairs. These results suggest that polymorphisms at these RAA axis loci do not make major contributions to the pathogenesis of renal disease in African Americans.
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PMID:Linkage analysis between loci in the renin-angiotensin axis and end-stage renal disease in African Americans. 898 34

The contractile response to bradykinin (BK), measured by the reduction of the planar surface area, was studied in glomeruli and mesangial cells (MC) isolated from diabetic rats (D) one week after diabetes induction with injection of streptozotocin (STZ; 60 mg kg-1, i.p.). Results were compared with age and weight-matched untreated rats (N) and were expressed by two parameters of cell activity, the mean maximum contraction (MMC) and the proportion of contractile cells (PCC). Glomerular and mesangial contraction were found to be clearly reduced in diabetic rats in response to 100 nM BK. The lower contractile response was associated with a decrease of both glomerular calcium uptake and mesangial cell intracellular calcium mobilization. The fact that cell pretreatment with two protein kinase C (PKC) inhibitors, phorbol 12-13 myristate acetate and calphostin, lowered normal cell contraction at the level of that found in diabetic MC without any significant effect in the latter, suggests the involvement of a PKC pathway, perhaps by a decrease of activatable PKC in diabetes. In addition, our results led to the first description of a possible role of the kallikrein-kinin system in the early glomerular hemodynamic changes occurring in diabetes. Insulin (1-200 nM) increased the contractile response of cultured diabetic cells (MMC), and in this case, it also increased the PCC. It must be stressed that the effect of 1 nM insulin on the former (88% increase) was very much smaller than its effect on the latter (103% increase). The combination of the two parameters (contraction index, CI) provided a realistic evaluation of the contractile capacities of the cell population of the cultures as a whole. The differences in this index between normal and diabetic cell populations, in the absence or presence of insulin, were strictly parallel to those found in intact glomeruli. Finally, our results further confirm (Ouardani et al., Biol. Cell 86, 127, (1996)) the limit of the first five cell passages within which cultured MC can be reasonably used for the study of contractile abnormalities occurring in the early steps of diabetic state.
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PMID:Decrease of bradykinin-induced glomerular contraction in diabetic rat: a new cellular interpretation. 924 84

The renal kallikrein-kinin system and the renin-angiotensin system are implicated in the pathogenesis of diabetic nephropathy. We have shown that renal kallikrein and renin gene expression are altered by diabetes. To investigate the cellular mechanisms responsible for these changes, we examined the effects of acute insulin and insulin-like growth factor I (IGF-I) treatment on renal kallikrein-kinin and renin-angiotensin system components. Three weeks after induction of diabetes, we measured renal kallikrein and renin mRNA levels, renal kallikrein and renal renin activity, and plasma renin activity in control and diabetic rats and diabetic rats treated with insulin or IGF-I for 2 or 5 h. In diabetic rats, kallikrein and renin mRNA levels were reduced >50% compared with control rats. Renal tissue kallikrein levels and plasma renin activity were decreased, whereas renal renin content was unchanged. Insulin increased kallikrein and renin mRNA levels after 2 h. IGF-I, at a dosage that stimulated kallikrein mRNA levels in control rats, had no effect on renal kallikrein and renin content or mRNA levels in diabetic rats. However, infusion of a fivefold higher IGF-I dosage resulted in a two- to threefold increase in kallikrein and renin mRNA levels in 2 h. These data suggest that 1) diabetes suppresses kallikrein and renin gene expression, and these abnormalities are reversed by insulin or IGF-I; and 2) the diabetic state produces resistance to IGF-I induction of kallikrein and renin gene expression. These changes in regulated synthesis of kallikrein and renin in the kidney may underlie renal vascular changes that develop in diabetes.
Diabetes 1997 Dec
PMID:Induction of renal kallikrein and renin gene expression by insulin and IGF-I in the diabetic rat. 939 95

Sub-diabetogenic doses of streptozotocin (STZ) produce insulitis, beta cell destruction and diabetes in mice. Since kinin have been proposed as an inflammatory mediator in several diseases, we decided to evaluate the role of the kallikrein-kinin system in the evolution of insulitis. Male C 57 BL/KsJ mdb mice were injected with STZ (40 mg/kg) for 5 consecutive d. Aprotinin (4000 KIU/d) was injected simultaneously with STZ during 10 d. Plasma and urine samples collected on day 15 were assayed for glucose concentration and proteins, nitrites and kallikrein. Diabetic mice showed hyperglycemia and increased diuresis, marked proteinuria, nitrites and kallikrein. Administration of aprotinin, a potent tissue kallikrein inhibitor, to STZ mice, reduced the hyperglycemia and the altered renal function of the diabetic mice to level no different from normal mice. The present studies are consistent with the hypothesis that the over-production of tissue kallikrein in insulitis could be controlled by the effect of aprotinin.
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PMID:Effects of aprotinin on the kallikrein-kinin system in type I diabetes (insulitis). 940 44

The aim of the study was to evaluate the role of urinary kallikrein in the regulation of renal hemodynamics and sodium handling in insulin-dependent diabetes mellitus (IDDM), and to test the effect of acutely induced hyperglycemia. Urinary kallikrein excretion was evaluated (1) under basal conditions and after stimulation with i.v. furosemide (0.5 mg x kg(-1)), (2) during glycemic clamp-induced eu- and hyperglycemia (5 and 12 mmol/L) and, (3) during time-controlled euglycemia in 21 short-term IDDM patients without microalbuminuria and in 18 weight-, age- and gender-matched healthy controls. Sodium excretion and renal hemodynamics using the clearances of inulin and para-amino-hippuric acid were measured during examinations in both groups. The baseline urinary kallikrein excretion during clamp-induced euglycemia was comparable in diabetic and control subjects (10.89+/-5.98 versus 10.38+/-3.73 mUE x min(-1)), whereas it was decreased in the baseline for furosemide (5.77+/-3.22 versus 10.9+/-3.7 mUE x min(-1); p < 0.01) and even after furosemide administration (12.0+/-1.6 versus 21.3+/-2.0 mUE x min(-1); p < 0.01) while the patients were hyperglycemic. During intravenous dextrose-induced hyperglycemia, the urinary kallikrein excretion significantly declined in diabetic patients (10.89+/-5.98 versus 5.45+/-0.88 mUE x min(-1); p < 0.01), whereas it did not change in controls (10.38+/-3.73 versus 12.55+/-5.47 mUE x min(-1)). A decrease in the fractional excretion of sodium and an attenuated rise in natriuresis after furosemide administration have been found in diabetic compared to control subjects. There were no significant relationships between kallikrein excretion and (1) renal hemodynamics, which was comparable in both groups, or (2) plasma renin activity, plasma and urine aldosterone and cortisol. We conclude that short-term IDDM without renal hemodynamic alterations is associated with decreased basal and furosemide-stimulated kallikrein excretion, which is directly related to the blood glucose level. The decreased activity of the renal kallikrein-kinin system might be involved in the increased tendency to sodium retention in diabetic patients.
J Diabetes Complications
PMID:Decreased urinary kallikrein with hyperglycemia in patients with short-term insulin-dependent diabetes mellitus. 974 43


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