Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous studies have investigated specific pathways that link diabetes and high extracellular glucose exposure to glomerulosclerosis and mesangial cell extracellular matrix production. However, only in the past ten years has a role for glucose transporters in this process been addressed. Many different glucose transporters are expressed in glomeruli; of these, the GLUT1 facilitative glucose transporter is upregulated in the diabetic renal cortex and in response to glomerular hypertension, as well as in cultured mesangial cells exposed to high glucose. Transgenic mouse and cell models have recently been developed to test the role of GLUT1 in the pathogenesis of glomerulosclerosis with and without diabetes. Clinical studies of GLUT1 alleles performed in humans have identified GLUT1 susceptibility alleles for diabetic nephropathy. Studies are also currently under way to assess the potential role of GLUT1 in nondiabetic renal disorders.
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PMID:Role for GLUT1 in diabetic glomerulosclerosis. 1651 29

Nephropathy is a major diabetic microvascular complication; both metabolic and hemodynamic perturbations play critical roles in its occurrence and progression toward end-stage renal disease. Improvements in metabolic and blood pressure control have been shown to confer protection from this diabetic complication. In this article, we review the facilitative glucose transporter Glut-1, its regulation, and its potential role in linking metabolic and hemodynamic perturbations in the pathophysiologic processes that lead to kidney injury in diabetes. We propose that an auto-maintaining mechanism of hemodynamic perturbations and increased tissue angiotensin II may be involved in the initiation and maintenance of a loop in which transforming growth factor beta1 and Glut-1 upregulation play important roles in the pathophysiology of diabetic-induced kidney lesions. The understanding of the molecular mechanisms that link glomerular hypertension and excessive glucose metabolism may provide insight into new therapeutic strategies for the treatment of diabetic renal disease.
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PMID:The link between Glut-1 and hypertension in diabetic nephropathy. 1660 Jan 63

We previously demonstrated that rats subjected to intermittent hypoxia (IH) by exposure to 10% O(2) for 4 h daily for 56 days in a normobaric chamber, developed pulmonary hypertension, right ventricular hypertrophy and wall-thickening in pulmonary arterioles, compared with normoxic (N) controls. These changes were greater in rats subjected to continuous hypoxia (CH breathing 10% O(2) for 56 days). Cerebral angiogenesis was demonstrated by immunostaining with glucose transporter 1 (GLUT1) antibody, in viable vessels, in CH and to a lesser degree in IH. In this study, adult Wistar rats were subjected to the same hypoxic regimes and given the nitric oxide synthase (NOS) inhibitor N(6)-nitro-L-arginine methyl ester (L-NAME) in drinking water (NLN, IHLN and CHLN regimes) to induce hypertension. There was significant systemic hypertension in NLN and IHLN rats, compared with N and IH, but surprisingly not in CHLN compared with CH. Hematocrit rose in all hypoxic groups (up to 79% in CHLN). There was no significant pulmonary hypertension in IHLN versus NLN rats, although there was asymmetric wall thickening in pulmonary arterioles. Cerebral GLUT1 immunoreactivity increased with L-NAME, with or without hypoxia, especially in CHLN rats, but conspicuously there was no evidence of angiogenesis in brains of IHLN compared with NLN rats. NOS blockade may attenuate the cerebral and pulmonary vascular changes of IH while augmenting cerebral angiogenesis in continuous hypoxia. However, whether cerebral effects are due to systemic hypertension or changes in cerebral nitric oxide production needs to be evaluated.
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PMID:Effects of NOS inhibition on the cardiopulmonary system and brain microvascular markers after intermittent hypoxia in rats. 1679 27

Arsenic exposure is associated with hypertension, diabetes, and cancer. Some mammals methylate arsenic. Saccharomyces cerevisiae hexose permeases catalyze As(OH)(3) uptake. Here, we report that mammalian glucose transporter GLUT1 catalyzes As(OH)(3) and CH(3)As(OH)(2) uptake in yeast or in Xenopus laevis oocytes. Expression of GLUT1 in a yeast lacking other glucose transporters allows for growth on glucose. Yeast expressing yeast HXT1 or rat GLUT1 transport As(OH)(3) and CH(3)As(OH)(2). The K(m) of GLUT1 is to 1.2mM for CH(3)As(OH)(2), compared to a K(m) of 3mM for glucose. Inhibition between glucose and CH(3)As(OH)(2) is noncompetitive, suggesting differences between the translocation pathways of hexoses and arsenicals. Both human and rat GLUT1 catalyze uptake of both As(OH)(3) and CH(3)As(OH)(2) in oocytes. Thus GLUT1 may be a major pathway uptake of both inorganic and methylated arsenicals in erythrocytes or the epithelial cells of the blood-brain barrier, contributing to arsenic-related cardiovascular problems and neurotoxicity.
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PMID:Mammalian glucose permease GLUT1 facilitates transport of arsenic trioxide and methylarsonous acid. 1706 64

Reduced insulin sensitivity is a key factor in the pathogenesis of type 2 diabetes and hypertension. Skeletal muscle insulin resistance is particularly important for its major role in insulin-mediated glucose disposal. Angiotensin II (ANG II) is integral in regulating blood pressure and plays a role in the pathogenesis of hypertension. In addition, we have documented that ANG II-induced skeletal muscle insulin resistance is associated with generation of reactive oxygen species (ROS). However, the linkage between ROS and insulin resistance in skeletal muscle remains unclear. To explore potential mechanisms, we employed the transgenic TG(mRen2)27 (Ren-2) hypertensive rat, which harbors the mouse renin transgene and exhibits elevated tissue ANG II levels, and skeletal muscle cell culture. Compared with Sprague-Dawley normotensive control rats, Ren-2 skeletal muscle exhibited significantly increased oxidative stress, NF-kappaB activation, and TNF-alpha expression, which were attenuated by in vivo treatment with an angiotensin type 1 receptor blocker (valsartan) or SOD/catalase mimetic (tempol). Moreover, ANG II treatment of L6 myotubes induced NF-kappaB activation and TNF-alpha production and decreased insulin-stimulated Akt activation and GLUT-4 glucose transporter translocation to plasma membranes. These effects were markedly diminished by treatment of myotubes with valsartan, the antioxidant N-acetylcysteine, NADPH oxidase-inhibiting peptide (gp91 ds-tat), or NF-kappaB inhibitor (MG-132). Similarly, NF-kappaB p65 small interfering RNA reduced NF-kappaB p65 subunit expression and nuclear translocation and TNF-alpha production but improved insulin-stimulated phosphorylation (Ser(473)) of Akt and translocation of GLUT-4. These findings suggest that NF-kappaB plays an important role in ANG II/ROS-induced skeletal muscle insulin resistance.
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PMID:Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. 1807 21

Glycemic control and diabetes duration are believed to be the most important risk factors for the development of diabetic microangiopathy; however, the rate of progression of nephropathy, retinopathy and polyneuropathy varies considerably among patients. Besides the presence of risk factors such as hypertension, dyslipidaemia and smoking, there is evidence suggesting that genetic predisposition plays a role in the susceptibility to microvascular complications. Based on underlying pathogenesis, polymorphisms of several candidate genes belonging to multiple pathways have been investigated, like the genes related to mechanisms of hyperglycaemia-induced damage (such as advanced glycation end-products and reactive oxygen species increased formation, augmented activity of the aldose reductase pathway); genes related to the renin-angiotensin system; genes coding for cytokines, growth factors and its receptors, glucose transporter; among many others. This article reviews some studies that corroborate the importance of the genetic background in the development of diabetic microangiopathy.
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PMID:[Genetic susceptibility to microangiopathy development in Type 1 diabetes mellitus]. 1843 49

The epidemic of Type 2 diabetes, and the parallel rising incidence of end-stage renal disease, is progressively increasing worldwide. Kidney disease is one of the major chronic microvascular complications of diabetes, and both metabolic and haemodynamic perturbations participate in its development and progression towards end-stage renal disease. Hypertension and poor metabolic control seem to interact in causing the relentless decline in renal function seen in diabetic patients. Both high circulating glucose levels and increased glomerular capillary pressure act in conjunction in stimulating the different cellular pathways leading to kidney disease. It has been suggested that mechanical forces at the glomerular level may aggravate the metabolic insult by stimulating excessive cellular glucose uptake by up-regulating the facilitative GLUT-1 (glucose transporter-1). We propose the existence of a self-maintaining cellular mechanism whereby a haemodynamic stimulus on glomerular cells induces the up-regulation of GLUT-1, an event followed by greater glucose uptake and activation of intracellular metabolic pathways, resulting in excess TGF-beta1 (transforming growth factor-beta1) production. TGF-beta1, one of the major prosclerotic cytokines in diabetic kidney disease, maintains the up-regulation of GLUT-1, perpetuating a series of cellular events that result, as their ultimate effect, in increased extracellular matrix synthesis and altered permeability of the glomerular filtration barrier. Mechanical and metabolic coupling could represent an important mechanism of injury in the diabetic kidney.
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PMID:Molecular mechanisms of proteinuria in diabetes. 1879 66

Progressive ventricular hypertrophy can lead to the development of insulin resistance, a feature of both chronic kidney disease and heart failure. Here we induced uremia in adult male Sprague-Dawley rats using a remnant kidney model and studied the expression of glucose transporters. As expected, the reduction of nephron mass resulted in impaired renal function, cardiac hypertrophy, glucose intolerance, hyperinsulinemia, anemia, and hypertension. Insulin sensitivity was significantly reduced in the uremic animals as determined by oral glucose tolerance tests. After six weeks of uremia, at a point when cardiac hypertrophy had been established, left ventricle tissue had a marked increase in the expression of GLUT4 (insulin-dependent glucose transporter 4), consistent with hypertrophic remodeling, but not GLUT1 (insulin-independent glucose transporter 1). However, although uremic animals had systemic insulin resistance and glucose intolerance, there was no evidence of impaired GLUT4 translocation in the heart at 6 weeks of uremia, suggesting that other mechanisms may underpin insulin resistance in the uremic heart.
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PMID:Insulin resistance and altered glucose transporter 4 expression in experimental uremia. 1917 56

Renin is the rate-limiting enzyme in renin-angiotensin system (RAS) activation. We sought to determine the impact of renin inhibition on whole-body insulin sensitivity and skeletal muscle RAS, oxidative stress, insulin signaling, and glucose transport in the transgenic TG(mRen2)27 rat (Ren2), which manifests increased tissue RAS activity, elevated serum aldosterone, hypertension, and insulin resistance. Young (aged 6-9 wk) Ren2 and age-matched Sprague Dawley control rats were treated with aliskiren [50 mg/kg . d, ip] or placebo for 21 d and administered an ip glucose tolerance test. Insulin metabolic signaling and 2-deoxyglucose uptake in soleus muscle were examined in relation to tissue renin-angiotensin-aldosterone system [angiotensin (Ang) II, mineralocorticoid receptor (MR), and Ang type I receptor (AT(1)R)] and measures of oxidative stress as well as structural changes evaluated by light and transmission electron microscopy. Ren2 rats demonstrated systemic insulin resistance with decreased skeletal muscle insulin metabolic signaling and glucose uptake. This was associated with increased Ang II, MR, AT(1)R, oxidative stress, and reduced tyrosine insulin receptor substrate-1 phosphorylation, protein kinase B/(Akt) phosphorylation and glucose transporter-4 immunostaining. The Ren2 also demonstrated perivascular fibrosis and mitochondrial remodeling. Renin inhibition improved systemic insulin sensitivity, insulin metabolic signaling, and glucose transport along with normalization of Ang II, AT(1)R, and MR levels, oxidative stress markers, fibrosis, and mitochondrial structural abnormalities. Our data suggest that renin inhibition improves systemic insulin sensitivity, skeletal muscle insulin metabolic signaling, and glucose transport in Ren2 rats. This is associated with reductions in skeletal muscle tissue Ang II, AT(1)R, and MR expression; oxidative stress; fibrosis; and mitochondrial abnormalities.
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PMID:Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression. 1924 35

GLUT9 is a novel, facilitative glucose transporter isoform that exists as two alternative splice variants encoding two proteins that differ in their NH(2)-terminal sequence (GLUT9a and GLUT9b). Both forms of GLUT9 protein and mRNA are expressed in the epithelia of various tissues; however, the two splice variants are expressed differentially within polarized cells, with GLUT9a localized predominantly on the basolateral surfaces and GLUT9b expressed on apical surfaces. Protein expression of GLUT9 drops under conditions of starvation but increases with addition of glucose and under hyperglycemic conditions. The substrate specificity of GLUT9 is unique since, in addition to transporting hexose sugars, it also is a high-capacity uric acid transporter. Several recent large-scale human genetic studies show a correlation between SNPs mapped to GLUT9 and the serum uric acid levels in several different cohorts. The relationship between GLUT9 and uric acid is highly clinically significant. Elevated uric acid levels have been associated with metabolic syndrome, obesity, diabetes, hypertension, and chronic renal failure. Although some believe uric acid is elevated as a result of these diseases, there is now evidence that uric acid may play a role in the pathogenesis of these diseases. It is also known that GLUT9 is expressed in articular cartilage and is a uric acid transporter, and thus it is possible that GLUT9 plays a role in gout, a disease of uric acid deposition in the joints. In addition, some studies have suggested that intake of fructose plays an important role in causing elevated serum uric acid levels, especially in diabetes and obesity. It is possible that GLUT9, which seems to be both a fructose and a uric acid transporter, plays an important role in these conditions associated with hyperuricemia.
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PMID:Facilitative glucose transporter 9, a unique hexose and urate transporter. 1979 40


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