Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral metabolism of glucose, one of the determinants of tissue ATP level, is crucial for central nervous system function. The activity of P-type pumps, namely Na(+), K(+) - ATPase, Ca(+2) - ATPase and Mg (+2) - ATPase were examined in brain synaptosomes of 5 - day, 3 - month and 18 - month - old rats to determine if changes in enzyme activity related to aging are potentially associated with alterations in glucose homeostasis. Activities of all the ATPases studied in isolated brain synaptosomes were expressed in micromol of Pi liberated from ATP by 1 mg of synaptosome protein during one hour. Serum glucose concentration was measured by the glucose oxidase method and insulin level was estimated by the RIA. Our results demonstrate that 18 - month - old rats are characterized by hyperglycemia and hyperinsulinemia. Their serum glucose concentration was significantly increased approx. 62.3% and 135.8 % as compared to 3 - month - old rats and 5 - day, newborn rats, respectively. An enormous increase in serum insulin concentration in the old, hyperglycemic rats was observed concomitantly. As a result of these changes the insulin - to - glucose ratio in the old rats was greatly increased approx. (270% and 230%) compared to young, mature and newborn rats. Hyperglycemia and hyperinsulinemia occurring in the old rats, had a different impact on activities of the ATPases tested. Our results have revealed that Na(+), K(+) - ATPase activity remains almost unchanged with age, the activity of Ca(+2) - ATPase decreases, whereas that of Mg(+2) - ATPase increases significantly in old, insulin resistant rats. In conclusion it seems that changes in activity of different P - type pumps may differ with aging and that adaptation of specific ATPases to internal environment alterations is not identical.
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PMID:Age-related changes of NA(+), K(+) - ATPase, Ca(+2) - ATPase and Mg(+2) - ATPase activities in rat brain synaptosomes. 1521 65

Chronic feeding of fructose to normal rats causes impaired glucose tolerance, loss of tissue sensitivity to insulin, hyperinsulinemia and hypertension. alpha-Lipoic acid (LA), a co-enzyme known for its potent antioxidant effects, stimulates insulin-mediated glucose uptake in clinical and experimental diabetes. The purpose of this study was to examine whether LA can mitigate fructose-induced insulin resistance and associated abnormalities. Male Wistar rats of body weights 150-170 g were divided into 4 groups containing 12 rats each. Control rats received a control diet containing starch and water ad libitum. Fructose rats received a fructose-enriched diet (>60% of total calories). Fructose + LA rats received a fructose diet and LA (35 mg/kg b.w.) intraperitoneally. Control + LA rats received a normal diet and LA (35 mg/kg b.w.) intraperitoneally. After the treatment period of 20 days, blood pressure (BP) was measured. Oral glucose-tolerance test, insulin-sensitivity index, urea and creatinine clearance tests, and plasma and urinary sodium and potassium levels were analysed. Kallikrein activity and nitrite content were assayed. Additionally, the activities of RBC-membrane Na(+)/K(+) ATPase and Ca(2+) ATPase enzymes were assayed. Fructose rats showed increased BP, decreased glucose tolerance, decreased insulin sensitivity and altered sodium and potassium levels and renal clearance. LA supplementation mitigated these alterations. The increase in BP was attenuated and the levels of biochemical parameters were brought close to normal. The BP-lowering effect of LA in fructose rats may be related to improvement in insulin sensitivity.
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PMID:Lipoic acid attenuates hypertension and improves insulin sensitivity, kallikrein activity and nitrite levels in high fructose-fed rats. 1556 49

Increased renal sodium retention is considered a major risk factor contributing to hypertension associated with chronic hyperinsulinemia and obesity. However, the molecular mechanism involved is not understood. The present study investigates the effect of insulin treatment on AT1 receptor expression and ANG II-induced stimulation of Na/H exchanger (NHE) and Na-K-ATPase (NKA) in opossum kidney (OK) cells, a proximal tubule cell line. The presence of the AT1 receptors in OK cells was confirmed by the specific binding of 125I-sar-ANG II and by detecting approximately 43-kDa protein on Western blot analysis with AT1 receptor antibody and blocking peptide as well as by expression of AT1 receptor mRNA as determined by RT-PCR. Insulin treatment (100 nM for 24 h) caused an increase in 125I-sar-ANG II binding, AT1 receptor protein content, and mRNA levels. The whole cell lysate and membrane showed similar insulin-induced increase in the AT1 receptor protein expression, which was blocked by genistein (100 nM), a tyrosine kinase inhibitor, and cycloheximide (1.5 microg/ml), a protein synthesis inhibitor. Determination of ethyl isopropyl amiloride-sensitive 22Na+ uptake, a measure of the NHE activity, revealed that ANG II (1-100 pM)-induced stimulation of NHE in insulin-treated cells was significantly greater than in the control cells. Similarly, ANG II (1-100 pM)-induced stimulation of ouabain-sensitive 86Rb+ uptake, a measure of NKA activity in insulin-treated cells, was significantly greater than in the control cells. ANG II stimulation of both the transporters was blocked by AT1 receptor antagonist losartan, suggesting the involvement of AT1 receptors. Thus chronic insulin treatment causes upregulation of AT1 receptors, which evoked ANG II-induced stimulation of NHE and NKA. We propose that insulin-induced increase in the renal AT1 receptor function serves as a mechanism responsible for the increased renal sodium reabsorption and thus may contribute to development of hypertension in conditions associated with hyperinsulinemia.
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PMID:Insulin treatment enhances AT1 receptor function in OK cells. 1571 8

In spite of a progressive fall in the incidence of traditional risk factors of cardiovascular morbidity (cigarette smoking, high blood pressure, and hyperlipidemia), there is an upward trend in the prevalence of obesity and chronic kidney disease (CKD). Furthermore, there is a strong correlation between body mass indices and the relative risk of progression of CKD. The close biophysiological interaction between obesity and CKD is evident by a similar occurrence of comorbidities including insulin resistance, hyperlipidermia, endothelial dysfunction, and sleep disorders. Truncal obesity is a primary component of metabolic syndrome; unlike peripheral fat, the visceral adipocytes are more resistant to insulin. In addition, lipolysis results in a release of free fatty acid and TG, whereas hypertriglycedemia is potentiated by uremic activation of fatty acid synthase. Hypertriglycedemia and low HDL cholesterol increase the relative risk of progression of CKD. Furthermore, endothelial inflammation and premature atherosclerosis are promoted by hyperhomocysteinemia and oxidation of LDL, both of which are commonly observed in CKD and obesity. Predominance of oxidative stress in both obesity and azotemia stimulate synthesis of angiotensin II, which in turn increases TGF-B and plasminogen activator inhibitor-1, thereby propagating glomerular fibrosis. Furthermore, local synthesis of angiotensinogen by adipocytes, leptin activation of sympathetic nervous system, and hyperinsulinemia contribute to the development of hypertension in obesity and CKD. In addition, increased renal tubular expression of Na-K-ATPase and a blunted response to natiuretic hormones in obesity promote salt and water retention. Glomerular hyperfiltration from systemic volume load and hypertension results in mesangial cellular proliferation and progressive renal fibrosis. In addition, maternal nutritional deprivation increases the incidence of obesity, hypertension, and diabetes in adulthood. Reduced fetal protein synthesis contributes to oxidative glomerular injury and impairment of renal morphogenesis. Thus, kidneys are poorly equipped to handle physiologic stress that may result from the rapid body growth and programmed metabolic dysfunction later in life. Finally, in order to minimize morbidity of obesity-related kidney disease, preventive strategy must include optimal maternal health care, promotion of healthy nutrition and routine physical exercise, and early detection of CKD.
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PMID:The role of obesity and its bioclinical correlates in the progression of chronic kidney disease. 1704 21

Hyperinsulinemia is reported to play a role in hypertension, as abnormalities in blood pressure regulation and sodium handling exist in diabetes mellitus. Kidney dopamine promotes sodium excretion via the activation of renal D1 receptors. Because there is a close relationship between renal D1 receptor function and sodium excretion, it is hypothesized that a defect in this mechanism may contribute to decreased sodium excretion and hypertension during hyperinsulinemia. Renal D1 receptor function was studied in insulin-induced hypertension in male Sprague Dawley rats. Insulin pellets were implanted subcutaneously for controlled insulin release for three weeks; sham rats served as a control. Compared to control rats, insulin pellets increased plasma insulin levels by eight fold and decreased blood glucose by 40%. Insulin also caused a 22 mmHg increase in mean arterial blood pressure compared to control animals. The intravenous infusion of SKF-38393, a D1 receptor agonist, increased sodium excretion in control rats, but SKF-38393 failed to produce natriuresis in hyperinsulinemic animals. Renal proximal tubules from hyperinsulinemic rats had a reduced D1 receptor number, defective receptor-G protein coupling, and blunted SKF-38393 induced Na, K-ATPase inhibition. Insulin seems to reduce D1 receptor expression and coupling to the G-protein, leading to a reduced D1 receptor-mediated Na, K-ATPase inhibition, and a diminished natriuretic response to SKF-38393. These phenomena could account for sodium retention and hypertension associated with hyperinsulinemia.
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PMID:Defective renal dopamine D1 receptor function contributes to hyperinsulinemia-mediated hypertension. 1713 36

Cerebral metabolism of glucose, one of the determinants of tissue ATP level, is crucial for the CNS function. The activity of P-type pumps: Na(+), K(+)-ATPase, Ca(+2)-ATPase and Mg(+2)-ATPase were examined in rat brain synaptosomes to determine if changes in the enzyme activity related to aging are potentially associated with alterations in glucose homeostasis. Male Wistar rats (newborn, 3- and 18-month-old) were sacrificed by decapitation and synaptic plasma membranes were isolated from brains. In vivo study demonstrated that 18-month-old rats were characterized by hyperglycemia, hyperinsulinemia and increased total antyoxidative status (TAS) level. These conditions had a different impact on activities of the ATPases tested in vivo: only the activity of Ca(+2)-ATPase decreased whereas that of Mg(+2)-ATPase increased significantly. In vitro experiments, prior incubation of isolated synaptosomes with glucose of concentrations corresponding to normoglycemia in vivo (4.5 - 6.5 mM), stimulated Ca(+2)-ATPase activity, whereas higher glucose concentrations (10.0 - 12.5 mM) inhibited significantly the enzyme activity. The most sensitive to hyperglycemia appeared Na(+), K(+)-ATPase in old rats synaptosomes with the progressive decline starting at 6.5 mM glucose. The activity of Mg(+2)-ATPase was not inhibited in vitro even at high glucose concentrations that may explain the increased in vivo, activity of this enzyme in old, hyperglycemic rats.
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PMID:In vivo and in vitro effects of hyperglycemia on Na+ -K+, Ca+2, Mg+2-dependent ATPases activity in brain synaptosomes of aging rats. 1722 2

The sodium(Na)- and potassium(K)-activated adenosine-triphosphatase (Na,K-ATPase) is a membrane enzyme that energizes the Na-pump by hydrolysing adenosine triphosphate and wasting energy as heat, so playing a role in thermogenesis and energy balance. Na,K-ATPase regulation by insulin is controversial; in tissue of hyperglycemic-hyperinsulinemic ob/ob mice, we reported a reduction, whereas in streptozotocin-treated hypoinsulinemic-diabetic Swiss and ob/ob mice we found an increased activity, which is against a genetic defect and suggests a regulation by hyperinsulinemia. In human adipose tissue from obese patients, Na,K-ATPase activity was reduced and negatively correlated with body mass index, oral glucose tolerance test-insulinemic area and blood pressure. We hypothesized that obesity is associated with tissue Na,K-ATPase reduction, apparently linked to hyperinsulinemia, which may repress or inactivate the enzyme, thus opposing thyroid hormones and influencing thermogenesis and obesity development. Insulin action on Na,K-ATPase, in vivo, might be mediated by the high level of non-esterified fatty acids, which are circulating enzyme inhibitors and increase in obesity, diabetes and hypertension. In this paper, we analyse animal and human tissue Na,K-ATPase, its level, and its regulation and behaviour in some hyperinsulinemic and insulin-resistant states; moreover, we discuss the link of the enzyme with non-esterified fatty acids and attempt to interpret and organize in a coherent view the whole body of the exhaustive literature on this complicated topic.
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PMID:Animal and human tissue Na,K-ATPase in normal and insulin-resistant states: regulation, behaviour and interpretative hypothesis on NEFA effects. 1744 65

The purpose of the study was to investigate the effects of L-carnitine (CA) on the susceptibility of erythrocyte (RBC) to peroxide-induced lipid oxidation, RBC membrane composition, ATPases activity and oxidative stress in fructose-fed hyperinsulinemic rats. The rats were subjected to experimental hyperinsulinemia and hyperglycemia by feeding a high fructose diet (60 g/100 g) for 6 weeks. The rats showed significant alterations in the RBC membrane composition. The protein content was lower than control animals, while cholesterol, phospholipids and free fatty acids were higher in fructose-fed animals. Significant differences in the total carbohydrate and relative proportions of hexose, hexosamine, sialic acid and fucose of membranes were observed. In these rats, membrane-bound ATPases (total ATPase, Na+, K+ ATPase, Mg2+ and Ca2+ ATPases) were significantly lower while thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LHP) in RBC membrane were significantly higher than those of control rats. The red cells were more susceptible to peroxide-induced oxidative stress that correlated with reduced levels of vitamin E found RBC membrane. When fructose-diet fed rats were treated simultaneously with CA (300 mg/kg b.w/day, i.p.), such alterations in membrane composition and enzyme activities did not occur. Effects of fructose loading on lipid peroxidation was also alleviated by CA. These findings suggest that high levels of dietary fructose is detrimental to RBC membrane integrity and that CA may have membrane stabilizing effects in this diet-induced model of type 2-diabetes.
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PMID:Effects of L-carnitine on RBC membrane composition and function in hyperinsulinemic rats. 1751 55

The renal dopamine system plays an important role in sodium homeostasis and a defect in dopamine D1 receptor (D1R) function is present in hypertension, diabetes, and aging. Our previous studies in hyperinsulinemic animals and in renal cell cultures treated with insulin showed decrease in D1R number and defective coupling to G proteins; however, the exact mechanisms remained unknown. Therefore, we investigated insulin-mediated D1R desensitization and underlying molecular mechanism in opossum kidney (OK) cells. Chronic exposure (24 h) of OK cells to 10 nM insulin caused significant decrease in D1R number and agonist affinity. The D1R was hyperserine phosphorylated, uncoupled from G proteins and SKF38393, a D1R agonist, failed to stimulate G proteins and inhibit Na-K-ATPase activity. Insulin increased protein kinase C (PKC) activity and caused G protein-coupled receptor kinase 2 (GRK2) translocation to the membranes. Tyrosine kinase inhibitor genistein and phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin blocked insulin-mediated PKC activation and GRK2 membranous translocation. In addition to genistein and wortmannin, GRK2 membranous tranlocation was also blocked by PKC inhibitor chelerythrine chloride and GRK2-specific siRNA. Genistein, wortmannin, chelerythrine chloride, and GRK2 siRNA abrogated D1R serine phosphorylation and normalized D1R expression and affinity in insulin-treated cells. Furthermore, these inhibitors and siRNA restored D1R G protein coupling and ability of SKF38393 to inhibit Na-K-ATPase activity. In conclusion, insulin-induced D1R desensitization involves PI3K, PKC, and GRK2. Insulin activates PI3K-PKC-GRK2 cascade, causing D1R serine phosphorylation, which leads to D1R downregulation and uncoupling from G proteins, and results in the failure of SKF38393 to stimulate G proteins and inhibit Na-K-ATPase activity.
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PMID:Insulin causes renal dopamine D1 receptor desensitization via GRK2-mediated receptor phosphorylation involving phosphatidylinositol 3-kinase and protein kinase C. 1756 39

Insulin has been shown to have antinatriuretic actions in humans and animal models. Moreover, endogenous hyperinsulinemia and insulin infusion have been correlated to increased blood pressure in some models. In this review, we present the current state of understanding with regard to the regulation of the major renal sodium transporters by insulin in the kidney. Several groups, using primarily cell culture, have demonstrated that insulin can directly increase activity of the epithelial sodium channel, the sodium-phosphate cotransporter, the sodium-hydrogen exchanger type III, and Na-K-ATPase. We and others have demonstrated alterations in the expression at the protein level of many of these same proteins with insulin infusion or in hyperinsulinemic models. We also discuss how this regulation is perturbed in type I and type II diabetes mellitus. Finally, we discuss a potential role for regulation of insulin receptor signaling in the kidney in contributing to sodium balance and blood pressure.
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PMID:Insulin's impact on renal sodium transport and blood pressure in health, obesity, and diabetes. 1768 57


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