Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CS-866 is a new angiotensin II receptor blocker that has demonstrated effectiveness for lowering blood pressure in animal models of hypertension. Given the proposed involvement of the renin-angiotensin system in diabetic nephropathy and atherosclerosis, we have tested CS-866 in animal models of these conditions. The renal protective properties of CS-866 were examined in the Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes that develops progressive hyperglycemia, glomerulosclerosis, and proteinuria. Treatment of ZDF rats with CS-866 in the diet for 19 weeks resulted in a dose-dependent reduction in urinary protein excretion compared with vehicle-treated control rats, which was independent of changes in blood pressure and glycemic state. The antiatherosclerotic properties of CS-866 were tested in 2 animal models. In the first study, cynomolgus monkeys were fed a high-cholesterol diet for 6 months while receiving CS-866 or vehicle. At the end of this period, CS-866-treated animals had 64% less plaque area in the aorta than controls. CS-866 was also tested in the Watanabe heritable hyperlipidemic (WHHL) rabbit model of atherosclerosis. WHHL rabbits were treated for 32 weeks with CS-866 (1 mg/kg), pravastatin (50 mg/kg), a combination of the 2 drugs, or vehicle. CS-866 had no effect on plasma cholesterol levels and reduced blood pressures minimally. Pravastatin alone reduced serum cholesterol but had no effect on blood pressure or lesion area. In contrast, treatment with CS-866 resulted in a 40% reduction in lesion area compared with vehicle-treated control when given alone and a 50% reduction in combination with pravastatin. On the basis of results from animal models, CS-866 may be a useful treatment for diabetic nephropathy and atherosclerosis.
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PMID:New pharmacologic aspects of CS-866, the newest angiotensin II receptor antagonist. 1133 66

Lipoprotein abnormalities are a regular part of metabolic changes associated with chronic renal failure. The character of dyslipoproteinaemia changes with the severity of disorders of renal functions, from initial deviations in the composition and distribution of circulating lipoprotein particles (a decline of glomerular filtration to 0.7-0.8 ml/s) to differently expressed changes of plasma lipid concentrations in terminal renal failure. The basis of the pathogenetic mechanism of these lipid abnormalities is the negative effect of the uraemic environment on the formation and catabolism of triglyceride-risk lipoproteins and on the function of the reverse cholesterol transport. An important part is also played by the modification of lipoprotein particles by oxidation and glycation. To a different extent also the nutritional status is manifested via the unfavourable composition of dietary fats, reduced effectiveness of antioxidant factors and in some instances also carnitine deficiency. Haemodialysis treatment and in particular peritoneal dialysis modify these lipid abnormalities. From the quantitative aspect renal dyslipoproteinaemia is not very striking, despite this its quantitative changes are important. It may have a negative impact on the progression of renal disease by its participation in the development of glomerular sclerosis and tubulointerstitial fibrosis. As one of the important risk factors it participates also in the acceleration of atherosclerosis in patients with chronic renal failure and in their much higher cardiovascular mortality as compared with the general population. These factors justify efforts to influence uraemic dyslipoproteinaemia. Fibrates or statins are indicated in conjunction with the supporting effect of diet and modification of the dialysis regimen. In tables and figures some results assembled by the authors are presented obtained in a group of dialyzed patients (characteristic of the lipid profile under basal conditions on fasting and after an oral lipid load and experience with influencing dysliopoproteinaemia by fenofibrates and atorvastatin).
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PMID:[Dyslipoproteinemia and chronic kidney failure]. 1134 48

Endothelial nitric oxide synthase (eNOS) serves a number of functions in the vasculature. In response to stimuli such as shear stress or acetylcholine, eNOS catalyses the production of nitric oxide (NO) from L-arginine. The NO diffuses across the endothelium into neighbouring smooth muscle and induces vasodilation. NO also acts locally to prevent platelet and leucocyte aggregation and inhibits vascular smooth muscle cell proliferation. It has been shown that mice lacking eNOS have decreased blood pressure, decreased heart rate and increased plasma renin activity. It has also been reported that NO production was reduced in patients with essential hypertension compared with normotensive individuals. In several animal models of renal disease (subtotal renal ablation, ureteral obstruction and diabetes), the administration of L-arginine, and probably the increase in NO synthesis, reduced the degree of glomerulosclerosis, ameliorated the changes in the tubulointerstitial compartment of the kidney and also decreased the infiltration of the kidney by invading macrophages. In summary, the L-arginine-NO pathway plays an important role in hypertension, renal disease, inflammation and atherosclerosis. This pathway also interacts with the renin-angiotensin system, the eicosanoid pathway, endothelin, cytokines and regulators of inflammation such as NF-kappaB.
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PMID:The role of nitric oxide in hypertension and renal disease progression. 1136 23

Diabetic Nephropathy (DN) is the commonest cause of end-stage renal failure (ESRF) in the Western world. Diabetic nephropathy follows a well outline clinical course, starting with microalbuminuria through proteinuria, azotaemia and culminating in ESRF. Before the onset of overt proteinuria, there are various renal functional changes including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetes. It has been postulated that DN occurs as a result of the interplay of metabolic and hemodynamic factors in the renal microcirculation. There is no doubt that there is a positive relationship between hyperglycaemia, which is necessary but not sufficient, and microvascular complications. The accumulation of advanced glycosylated end-products (AGEs), the activation of isoform(s) of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycemia damages tissue. PKC is one of the key signaling molecules in the induction of the vascular pathology of diabetes. The balance between extracellular matrix production and degradation is important in this context. Transforming growth factor-beta (TGF-beta) appears to play a pivotal role in accumulation in the diabetic kidney. Hemodynamic disturbances are believed to be directly responsible for the development of glomerulosclerosis and its attendant proteinuria. There is familial clustering of diabetic kidney disease. A number of gene loci have been investigated to try to explain the genetic susceptibility to diabetic nephropathy. The genes coding for components of renin-angiotensin system have drawn special attention, due to the central role that this system plays in the regulation of blood pressure, sodium metabolism, and renal hemodynamics. Endothelial dysfunction is closely associated with the development of diabetic retinopathy, nephropathy and atherosclerosis, both in IDDM and in NIDDM. The pathogenesis of diabetic nephropathy is not clarified completely yet.
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PMID:Pathogenesis of diabetic nephropathy. 1146 May 89

A proposed analogy between atherosclerosis and glomerulosclerosis suggests that factors that contribute to the development of atherosclerosis, ie, oxidatively modified (lipo)proteins, may also participate in glomerular injury. Although the nature of the in vivo oxidants has not been clearly identified, increasing evidence suggested the myeloperoxidase (MPO)-H(2)O(2)-halide system to be responsible for the damage observed in leukocyte-dependent glomerulonephritis. MPO, a heme protein secreted by activated phagocytes, may generate modified/oxidized proteins in vivo via intermediate formation of hypochlorous acid (HOCl)/hypochlorite. HOCl, a reactive oxygen species and powerful oxidant, can convert (lipo)proteins into atherogenic forms in vitro and in vivo. Here we demonstrate the presence of HOCl-modified proteins in glomeruli of patients with membranous glomerulonephritis using monoclonal antibodies that do not cross-react with other oxidative modifications. Immunostaining for HOCl-modified epitopes in human minimal change glomerulopathy revealed glomeruli that were unreactive, although the number of MPO-positive cells/glomerulus was slightly increased in comparison to controls. In contrast to minimal change glomerulopathy, a pronounced infiltration of mononuclear cells/glomerulus in membranoproliferative glomerulonephritis is in line with pronounced staining for HOCl-modified epitopes. Immunostaining was detected in intracapillary cells and immune complex deposits within the glomerular basement membrane. In human membranous glomerulonephritis (Stages I to III), staining for HOCl-modified proteins was localized at the basement membrane and podocytes. Staining of serial sections revealed colocalization of HOCl-modified epitopes and MPO in glomerular peripheral basement membranes. Subsequently, tubulointerstitial staining for HOCl-modified epitopes was observed in foam cells at the border of the cytoplasm and in damaged tubular epithelia in focal advanced chronic lesions. Our results indicate that oxidative modification of the basement membrane structure by phagocyte-derived HOCl may be of importance for glomerular defects. The observed colocalization of HOCl-modified proteins and MPO in podocytes and adjacent basement membranes strengthens the assumption that the MPO-H(2)O(2)-halide system contributes to glomerular dysfunction in patients with membranous glomerulonephritis.
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PMID:Immunohistochemical detection of hypochlorite-modified proteins in glomeruli of human membranous glomerulonephritis. 1179 21

The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.
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PMID:Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1. 1190 42

The coexistence of hypercholesterolaemia and diabetes dramatically and synergistically increases the risk of microvascular and macrovascular complications in patients. A single unifying mechanism of increased production of reactive oxygen species (ROS) by angiotensin II (Ang II) may serve as a causal link between hyperglycaemia and hypercholesterolaemia and many of the major pathways responsible for atherogenic and diabetic disorders. Several lines of evidence suggest a crucial role for Ang II-mediated oxidative stress in the pathogenesis of hyperglycaemia- and hypercholesterolemia-associated endothelial dysfunction. Endothelial dysfunction in these scenarios may be due to impaired nitric oxide (NO) synthesis and/or inactivation of endothelium-derived NO by ROS. That Ang II plays an important role in the development of atherosclerosis and glomerulosclerosis is supported by numerous studies indicating that angiotensin receptor blockers (ARBs) retard the progression of these diseases in both experimental animal models and humans. Evidence indicates that Ang II contributes to atherogenesis at both transcriptional and translational levels by upregulating adhesion molecule mRNA and protein synthesis. The recent demonstration of Ang II AT(2) receptors in the adult kidney and their potential to oppose the vasoconstrictive, antinatriuretic, and profibrotic properties of AT(1) receptors suggests that the balance of intrarenal AT(1) and AT(2) receptors may be important in determining the cellular responses to Ang II in diabetic nephropathy. Results of these studies suggest that hypercholesterolaemia and hyperglycaemia can induce a pro-inflammatory response within coronary arteries and the kidney glomerulus. This response involves production of well described macrophage chemotactic and adhesion molecules, which results in macrophage recruitment and the development of acute and chronic injury. Glomerular macrophage recruitment in experimental diabetes occurs via Ang II-stimulated monocyte chemoattractant protein (MCP)-1 expression, suggesting that the renin-angiotensin system is an important regulator of local MCP-1 expression, and strongly implicating macrophage recruitment and activation in the pathogenesis of early diabetic glomerular injury. Diabetes-associated vascular complications may also involve an activation of the nuclear factor (NF)-kappaB by hyperglycaemia. NF-kappaB activation is related to AT(1) receptor-mediated pathways, and is believed to be dependent on activation of the Rho proteins belonging to the superfamily of low molecular weight guanosine triphosphatases (GTPases) that regulate intracellular signalling. Preincubation of vascular smooth muscle cells with insulin doubled NF-kappaB transactivation stimulated by Ang II and hyperglycaemia, suggesting a potential mechanism for crosstalk between the renin-angiotensin system and hyperglycaemia. Taken together, these data suggest that activation of the renin-angiotensin system is a mechanism for the initiation and progression of inflammatory cell infiltration found in early changes common to both hypercholesterolaemia and hyperglycaemia. While the base of information regarding ARBs in high-risk patients with diabetes and hypercholesterolemia is lacking, preclinical and pilot trial data suggest that the ARBs are reno- and vasculoprotective in these patients. Therapeutic blockade of Ang II AT(1) receptors in diabetic and hypercholesterolaemic humans by ARBs, with concomitant elevation in plasma and tissue Ang II levels, may provide vascular and renal protection not only by reducing AT(1) receptor-mediated pro-oxidative effects, but also by unopposed AT(2) receptor stimulation.
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PMID:[Pathophysiological and clinical implications of AT(1) and AT(2) angiotensin II receptors in metabolic disorders: hypercholesterolaemia and diabetes]. 1203 87

Kidney mesangial cells (MCs) and vascular smooth muscle cells (VSMCs) are closely related in terms of origin, microscopic anatomy, histochemistry, and contractility. This relationship suggests a similarity between kidney glomerular sclerosis and atherosclerosis. Vitamin E appears beneficial in the prevention and treatment of coronary disease and also inhibits the proliferation of VSMCs in vitro. We used vitamin E and probucol to treat glomerular sclerosis and MC-proliferative glomerulonephritis (GN) in two animal models of glomerular disease. Using rats, a remnant kidney model accelerated with hyperlipidemia was employed to reflect progressive glomerular sclerosis leading to chronic renal failure, and an anti-thymocyte serum treatment was used to model acute MC-proliferative GN. Supplemental dietary antioxidants suppress MC proliferation and glomerular sclerosis in models of glomerular disease in rats. These results suggest that treatment with antioxidants may be a promising intervention to prevent progression of kidney disease.
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PMID:Effects of antioxidants on kidney disease. 1204 53

Nephrotic dyslipidemia is a risk factor for the development of systemic atherosclerosis, and may aggravate glomerulosclerosis and enhance progression of glomerular disease. The greatest and most consistent reductions in LDL-cholesterol are achieved with HMG-CoA reductase inhibitors but their efficacy and safety in long-term therapy need to be evaluated. In this study, we gave fluvastatin to 21 nephrotic patients and followed then up clinically, neurophysiologically and by laboratory tests. There was an improvement in the lipogram, with reductions of triglycerides (TG) (33%) and LDL (35%) at three months. There was no clinical manifestation of myopathy and CPK was normal. Electromyographic data showed significant decreases in the amplitude and duration of motor unit action potentials in the proximal muscles with statin therapy, but these changes did not amount to classic myopathy. We conclude that fluvastatin is a safe drug for long-term use in dyslipidemic nephrotic patients. However, we suggest further studies to verify whether the early electromyography (EMG) changes observed in this study may progress or not on its longer term use.
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PMID:Neuromuscular toxicity in nephrotic patients treated with fluvastatin. 1249 86

Type 1 diabetes mellitus is associated with the development of micro- and macrovascular disease, and diabetic angiopathy in children and adolescents. It is represented mainly by microangiopathy, characterised by structural changes in the eye, renal glomeruli and peripheral nerves. The pathogenesis of the vascular complications of diabetes is controversial, but without any doubt, endothelial dysfunction play an important role in the pathogenesis of glomerulosclerosis and atherosclerosis. Preventive strategies for these three major complications are discussed in this review. Appropriate surveillance for the earliest evidence of microvascular disease should begin at the onset of puberty, and after 3 - 5 years of diabetes. Therapeutic interventions, particularly excellent metabolic control, may be almost effective in preventing complication onset, or significantly retarding the rate of progression.
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PMID:Preventing microvascular diabetic complications in children and adolescents: looking beyond glycaemic control. 1266 15


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