Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Considering the growing importance of the interaction between components of kallikrein-kinin and renin-angiotensin systems in physiological and pathological processes, particularly in diabetes mellitus, the aim of the present study was to investigate the effect of enalapril on the reduced response of bradykinin and on the interaction between angiotensin-(1-7) (Ang-(1-7)) and bradykinin (BK), important components of these systems, in an insulin-resistance model of diabetes. For the above purpose, the response of mesenteric arterioles of anesthetized neonatal streptozotocin-induced (n-STZ) diabetic and control rats was evaluated using intravital microscopy. In n-STZ diabetic rats, enalapril treatment restored the reduced response to BK but not the potentiation of BK by Ang-(1-7) present in non-diabetic rats. The restorative effect of enalapril was observed at a dose that did not correct the altered parameters induced by diabetes such as hyperglycemia, glicosuria, insulin resistance but did reduce the high blood pressure levels of n-SZT diabetic rats. There was no difference in mRNA and protein expressions of B1 and B2 kinin receptor subtypes between n-STZ diabetic and control rats. Enalapril treatment increased the B2 kinin receptor expression. From our data, we conclude that in diabetes enalapril corrects the impaired BK response probably by increasing the expression of B2 receptors. The lack of potentiation of BK by Ang-(1-7) is not corrected by this agent.
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PMID:Enalapril treatment corrects the reduced response to bradykinin in diabetes increasing the B2 protein expression. 1819 Sep 98

Diabetic retinopathy and diabetic nephropathy are common microvascular complications of diabetes. The kallikrein-kinin system (KKS) has been implicated in the development of both conditions, and, in particular, bradykinin and its receptors have been shown to exert angiogenic and proinflammatory actions. Several of the key processes that underlie the development of diabetic retinopathy, such as increased vascular permeability, edema, neovascularization, and inflammatory changes, have been associated with the KKS, and recent work has shown that components of the KKS, including plasma kallikrein, factor XIIa, and high-molecular-weight kininogen, are present in the vitreous of people with diabetic retinopathy. The role of the KKS in the development of diabetic nephropathy is controversial, with both adverse and protective effects of bradykinin and its receptors reported. The review examines the role of the KKS in pathways central to the development of diabetic retinopathy and compares this with reported actions of this system in diabetic nephropathy. The possibility of therapeutic intervention targeting bradykinin and its receptors as treatment for diabetic microvascular conditions is considered.
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PMID:The kallikrein-kinin system in diabetic retinopathy: lessons for the kidney. 1827 58

An understanding of the diabetes-induced alterations in vitreous protein composition in the absence and in the presence of proliferative diabetic retinopathy (PDR) may provide insights into factors and mechanisms responsible for this disease. We have performed a comprehensive proteomic analysis and comparison of vitreous samples from individuals with diabetes but without diabetic retinopathy (noDR) or with PDR and nondiabetic individuals (NDM). Using preparative one-dimensional SDS-PAGE and nano-LC/MS/MS of 17 independent vitreous samples, we identified 252 proteins from human vitreous. Fifty-six proteins were differentially abundant in noDR and PDR vitreous compared with NDM vitreous, including 32 proteins increased and 10 proteins decreased in PDR vitreous compared with NDM vitreous. Comparison of noDR and PDR groups revealed increased levels of angiotensinogen and decreased levels of calsyntenin-1, interphotoreceptor retinoid-binding protein, and neuroserpin in PDR vitreous. Biological pathway analysis revealed that vitreous contains 30 proteins associated with the kallikrein-kinin, coagulation, and complement systems. Five of them (complement C3, complement factor I, prothrombin, alpha-1-antitrypsin, and antithrombin III) were increased in PDR vitreous compared with NDM vitreous. Factor XII was detected in PDR vitreous but not observed in either NDM or noDR vitreous. PDR vitreous also had increased levels of peroxiredoxin-1 and decreased levels of extracellular superoxide dismutase, compared with noDR or NDM vitreous. These data provide an in depth analysis of the human vitreous proteome and reveal protein alterations that are associated with PDR.
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PMID:Characterization of the vitreous proteome in diabetes without diabetic retinopathy and diabetes with proliferative diabetic retinopathy. 1843 56

All the components of the kallikrein-kinin system are located in the cardiac muscle and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction, and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin-converting enzyme inhibitors is primarily mediated via a kinin-releasing pathway, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it a promising candidate in treating hypertension and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders. However, there are also possibilities of adverse effects that may be caused by these compounds.
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PMID:Cardiovascular activities of the bradykinin system. 1845 46

Diabetic cardiomyopathy is a specific cardiomyopathy which develops in patients with diabetes mellitus in the absence of coronary atherosclerosis and hypertension. Despite the potential importance of this disease entity, the underlying mechanisms are only incompletely understood. Changes in calcium handling, disruption of the extracellular matrix regulation with accumulation of cardiac collagen, and furthermore cardiac inflammation may be an important mediator of this disease. This brief review focuses on the current aspects of the kallikrein-kinin system and its influence on the development of diabetic cardiomyopathy with particular regard to the kinin receptors B1 and B2, as their role in the development of this disease is still under discussion. Whether the role of the B1 receptor is similar to the well-described beneficial role of the B2 receptor or whether its function is opposed to the B2 receptor is controversial. Some recent findings suggest that the B1 receptor mediates cardiac inflammation and therefore may be detrimental for cardiac function in the setting of diabetic cardiomyopathy.
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PMID:Development of diabetic cardiomyopathy and the kallikrein-kinin system--new insights from B1 and B2 receptor signaling. 1862 88

Since kallikrein was discovered as a vasodilatory substance in human urine, the kallikrein-kinin system (KKS) has been considered to play a physiological role in controlling blood pressure. Gene targeting experiments in mice in which the KKS has been inactivated to varying degrees have, however, questioned this role, because basal blood pressures are not altered. Rather, these experiments have shown that the KKS has a different and important role in preventing changes associated with normal senescence in mice, and in reducing the nephropathy and accelerated senescence-associated phenotypes induced in mice by diabetes. Other experiments have shown that the KKS suppresses mitochondrial respiration, partly by nitric oxide and prostaglandins, and that this suppression may be a key to understanding how the KKS influences senescence-related diseases. Here we review the logical progression and experimental data leading to these conclusions, and discuss their relevance to human conditions.
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PMID:The kallikrein-kinin system in health and in diseases of the kidney. 1919 Jun 76

Tissue kallikrein is the main kinin-forming enzyme in mammals, and differences in kinin levels are thought to be a contributing factor to diabetic nephropathy. Here, we determined the role of the kallikrein-kinin system in the pathogenesis of streptozotocin-induced diabetic nephropathy in wild-type and tissue kallikrein-knockout mice. All diabetic mice developed similar hyperglycemia, but the knockout mice had a significant two-fold increase in albuminuria compared to the wild-type mice before and after blood pressure elevation. Ezrin mRNA, a podocyte protein potentially implicated in albuminuria, was downregulated in the kidney of knockout mice. One month after induction of diabetes, the mRNAs of kininogen, tissue kallikrein, kinin B1, and B2 receptors were all increased up to two-fold in the kidney in both genotypes. Diabetes caused a 50% decrease in renal angiotensin-converting enzyme expression and a 20-fold increase in kidney injury molecule-1 reflecting tubular dysfunction, but there was no genotype difference. Our study found an early activation of the kallikrein-kinin system in the kidney and that this has a protective role against the development of diabetic nephropathy. The effect of tissue kallikrein deficiency on microalbuminuria in diabetic mice is similar to the effect of genetically high angiotensin-converting enzyme levels, suggesting that both observations, in part, result from a deficiency in kinins.
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PMID:Kallikrein protects against microalbuminuria in experimental type I diabetes. 1951 48

Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus that can lead to visual impairment and blindness. There is no approved pharmacological treatment for DR; however, laser therapy, steroids and anti-VEGF agents appear to provide some benefit. Hyperglycemia, advanced glycation end products, growth factors, and elevated levels of circulating and vitreous cytokines and chemokines can all trigger an inflammatory response of the retinal vasculature. Features of DR can include diabetic macular edema, microhemorrhage, loss of capillaries, development of avascular areas and the vitreo-retinal proliferation of neovessels. The kallikrein-kinin system (KKS) has long been recognized as a key player of inflammatory processes in various organs. Intravitreally administered recombinant plasma kallikrein has been demonstrated to produce retinal vascular leakage and hemorrhage, while both kinin B1 and B2 receptor agonists have induced retinal edema. Furthermore, kallikrein inhibitors and peptide-based B1 receptor antagonists could reduce or block retinal vascular permeability in diabetic rats. In a diabetic rat model, FOV-2304 (Fovea Pharmaceuticals SA), a non-peptide selective B1 receptor antagonist, consistently blocked retinal vascular permeability, inhibited leukocyte adhesion and abolished the retinal mRNA expression of several inflammatory mediators. Although additional studies are required to investigate the role of the KKS in early capillary loss and late-stage neovascularization processes, the blockade of the KKS is a promising therapeutic strategy for DR.
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PMID:Targeting the kallikrein-kinin system as a new therapeutic approach to diabetic retinopathy. 2041 96

An insertion polymorphism of the angiotensin-I converting enzyme gene (ACE) is common in humans and the higher expressing allele is associated with an increased risk of diabetic complications. The ACE polymorphism does not significantly affect blood pressure or angiotensin II levels, suggesting that the kallikrein-kinin system partly mediates the effects of the polymorphism. We have therefore explored the influence of lack of both bradykinin receptors (B1R and B2R) on diabetic nephropathy, neuropathy, and osteopathy in male mice heterozygous for the Akita diabetogenic mutation in the insulin 2 gene (Ins2). We find that all of the detrimental phenotypes observed in Akita diabetes are enhanced by lack of both B1R and B2R, including urinary albumin excretion, glomerulosclerosis, glomerular basement membrane thickening, mitochondrial DNA deletions, reduction of nerve conduction velocities and of heat sensation, and bone mineral loss. Absence of the bradykinin receptors also enhances the diabetes-associated increases in plasma thiobarbituric acid-reactive substances, mitochondrial DNA deletions, and renal expression of fibrogenic genes, including transforming growth factor beta1, connective tissue growth factor, and endothelin-1. Thus, lack of B1R and B2R exacerbates diabetic complications. The enhanced renal injury in diabetic mice caused by lack of B1R and B2R may be mediated by a combination of increases in oxidative stress, mitochondrial DNA damage and over expression of fibrogenic genes.
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PMID:Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice. 2047 36

Recent proteomic studies have identified components of the kallikrein kinin system, including plasma kallikrein, factor XII, and kininogen, in vitreous obtained from individuals with advanced diabetic retinopathy. In rodent models, activation of plasma kallikrein in vitreous increases retinal vascular permeability; whereas inhibition of the kallikrein kinin system reduces retinal leakage induced by diabetes and hypertension. These findings suggest that intraocular activation of the plasma kallikrein pathway may contribute to excessive retinal vascular permeability that can lead to diabetic macular edema. The kallikrein kinin system contains two separate and independently regulated serine proteases that generate bradykinin peptides: plasma kallikrein and tissue kallikrein. Tissue kallikrein is expressed in the retina and ciliary body, where it has been implicated in exerting autocrine or paracrine effects via bradykinin receptors that are colocalized in these tissues. Emerging evidence suggests that plasma kallikrein inhibitors may provide a new therapeutic opportunity to reduce retinal vascular permeability.
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PMID:Plasma kallikrein and diabetic macular edema. 2053 47


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