Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ET-1, ET-2 and ET-3) are a family of 21 amino acid peptides produced by endothelial cells. They are thought to regulate the local vasomotor tone with endothelium-derived relaxing factors. ETs are the most potent vasoconstrictor substances yet identified and veins and renal vasculature are the most sensitive targets. They reduce cardiac output and have positive inotropic and chronotropic effects. ETs increase the secretion of atrial natriuretic peptide (ANP), aldosterone and catecholamines but reduce renal blood flow and glomerular filtration and they also have mitogenic properties. ETs bind to receptors (ETA and ETB), activate phospholipase C, modulate intracellular Ca2+ concentration and open Ca2+ channels. Vasoactive agents (adrenaline, angiotensin, vasopressin, thrombin, endotoxins) and hypoxia stimulate the release of ET and also ET gene expression. Raised concentrations of plasma ET have been found to occur in several clinical conditions such as hypertension, myocardial infarction, cardiogenic shock, pregnancy induced hypertension, arteriosclerosis, Raynaud's disease, subarachnoid haemorrhage, uraemia, ulcerative colitis, Crohn's disease and surgical operations suggesting that ETs have a role in several patophysiological processes.
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PMID:Endothelin peptides: biological activities, cellular signalling and clinical significance. 138 14

Predicting the course of parathormone (PTH)-elicited bone turnover in both humans and experimental rat models with moderate chronic uremia, using only standard clinical chemistry analyses, is often difficult. Consequently, rat bone from 1 + 2/3 nephrectomized animals, after 230 days of progressive renal failure, was examined for PTH-stimulated adenylate cyclase (AC) and phospholipase C (PL-C) activities. Correlations to biological parameters related to the function of bone and kidney were made. Reduced renal function was demonstrated by increased serum creatinine; circulating 1,25 dihydroxyvitamin D3 below detection level; diminished renal PTH-elicited AC activity; and decreased urinary cAMP excretion. PTH-activated renal PL-C was also reduced. However, no significant differences were seen in urine creatinine, calcium, phosphate, and hydroxyproline, nor in serum PTH, alkaline phosphatase, calcium, and phosphate. Notwithstanding, renal osteodystrophy developed as estimated by increased plasticity of the long bones, as well as reduction of the diaphyseal (Dd) and inner femoral mid-shaft (Di) diameters. Femoral cancellous bone exhibited a substantial elevation of both eroded surface (ES) and osteoid surface (OS) as well as a marked reduction in trabecular bone volume (TBV). Calvarial PTH-activated AC was enhanced, whereas corresponding PL-C was markedly reduced. PTH-enhanced AC correlated positively with ES and negatively with Di, respectively. PTH-enhanced PL-C, however, correlated positively with bone calcium content and negatively with ES. Our results indicate that bone modeling and remodeling are to a large extent related to PTH-elicited signaling systems, and cannot easily be predicted by standard clinical chemistry analyses.
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PMID:Surgically induced uremia in rats. II: Osseous PTH-susceptible signaling systems as predictors of bone resorption. 782 Jul 79

We have previously established an uremic rat model which is suitable for investigating the effect of various treatment modalities on the progression of renal osteodystrophy [1]. Four months subsequent to 5/6 nephrectomy, animals were treated three times a week for 3 months with either vehicle, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 1,25(OH)2D3 + 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25(OH)2D3 + calcitonin (CT), or 1,25(OH)2D3 + 24,25(OH)2D3 + CT. At termination of the study, clinical chemistry, chemical composition, and mechanical properties of femurs, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC), and phospholipase C (PL-C) activities, femoral cross-sectional area, and bone histomorphometry were analyzed. The main findings were that 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment enhanced elasticity as well as time to fracture at the femoral metaphysis. CT potentiated the increase in elasticity obtained by 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment. Only 24,25(OH)2D3 administration rectified the supernormal PTH-stimulated uremic bone AC, and only 1,25(OH)2D3 medication normalized the diminished CT-elicited AC. The obliterated uremic bone PTH-sensitive PL-C was fully normalized by all drug regimens. Femoral shaft inner zone diameter was enhanced by uremia, however, all drug treatments normalized it. Ditto effect was registered with either drug treatment on the subnormal outer and inner zone widths. Histomorphometrical analyses showed that 1,25(OH)2D3 administration reduced both eroded and osteoid surfaces. Most prominently, adjuvant 24,25(OH)2D3 or CT administration potentiated the beneficial effect of 1,25(OH)2D3 on fibrosis and osteomalacia. We assert that vitamin D3 treatment markedly reverses the development of renal osteodystrophy, and CT potentiates the effect of vitamin D3.
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PMID:Vitamin D3 analogs and salmon calcitonin partially reverse the development of renal osteodystrophy in rats. 856 2

We have previously established a rat model of chronic uremia, which is suitable to investigate the effect of various treatment modalities on renal osteodystrophy [1]. After four months subsequent to 5/6 nephrectomy, some animals were treated by gavage for 9 weeks with tap water (controls), or with aluminium (Al-citrate) 3 x 25 mg/week/kg b.wt +/- subsequent deferoxamine (DFO) 3 x 50 mg/week/kg b.wt. for 4 weeks. At termination of the study, serum clinical chemistry, femoral chemical composition and mechanical properties, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC) and phospholipase C (PLC) activities, cross-sectional femoral area, as well as bone histomorphometry, were analyzed. Animals given Al displayed moderately enhanced serum Al and bone Al accumulation, however, DFO-treatment did not fully alleviate bone Al retainment. A small increase in serum PTH was seen in all animals rendered uremic. Furthermore, a marked fall in serum alkaline phosphatase (ALP) below normal controls was observed in Al +/- DFO-treated animals compared with uremic controls. The uremic condition led to reduced femoral ratios of hydroxyproline (HYP) over Ca(2+) and phosphate (P(i)), while Al-intoxication alone enhanced femoral Hyp contents above values seen for normal controls. The protracted ureamia caused a deterioration of long bone resilience and brittleness, however, Al +/- DFO-treatment seemed to normalize the latter. Contrastingly, Al +/- DFO-gavage enhanced time to fracture. Uremic rats intoxicated with Al showed a complete loss of calvarial PTH-sensitive AC and PLC activities. DFO-treatment normalized PTH-elicited PLC, while PTH-susceptible AC remained super-normal. Al apparently exerts a long term down-regulation of both PTH-sensitive signaling systems as evidenced by studies of rat UMR 106 osteosarcoma cells in culture. The uremic condition enhanced endosteal bone resorption as shown by femoral shaft dimension analysis, while Al +/- DFO-treatment insignificantly reversed the condition. Finally, histomorphometrical analyses showed that DFO-administration tended to normalize aberrant trabecular bone volume, while rectifying both bone resorption and degree of mineralization. In conclusion, we assert that Al-intoxication hampers both processes (i.e. formation and resorption) of bone turnover, and that DFO-treatment to a certain extent prevents the uremia- and Al-induced bone disease in rats.
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PMID:Aluminium-induced bone disease in uremic rats: effect of deferoxamine. 886 40

Endogenous cardiotonic glycosides bind to the inhibitory binding site of the plasma membrane sodium pump (Na(+)/K(+)-ATPase). Plasma levels of endogenous cardiotonic glycosides increase in several disease states, such as essential hypertension and uremia. Low concentrations of ouabain, which do not inhibit Na(+)/K(+)-ATPase, induce cell proliferation. The mechanisms of ouabain-mediated response remain unclear. Recently, we demonstrated that in opossum kidney (OK) proximal tubular cells, low concentrations of ouabain induce cell proliferation through phosphorylation of protein kinase B (Akt) in a calcium-dependent manner. In the present study, we identified ERK as an upstream kinase regulating Akt activation in ouabain-stimulated cells. Furthermore, we provide evidence that low concentrations of ouabain stimulate Na(+)/K(+)-ATPase-mediated (86)Rb uptake in an Akt-, ERK-, and Src kinase-dependent manner. Ouabain-mediated ERK phosphorylation was inhibited by blockade of intracellular calcium release, calcium entry, tyrosine kinases, and phospholipase C. Pharmacological inhibition of phosphoinositide-3 kinase and Akt failed to inhibit ouabain-stimulated ERK phosphorylation. Ouabain-mediated Akt phosphorylation was inhibited by U0126, a MEK/ERK inhibitor, suggesting that ouabain-mediated Akt phosphorylation is dependent on ERK. In an in vitro kinase assay, active recombinant ERK phosphorylated recombinant Akt on Ser(473). Moreover, transient transfection with constitutively active MEK1, an upstream regulator of ERK, increased Akt phosphorylation and activation, whereas overexpression of constitutively active Akt failed to stimulate ERK phosphorylation. Ouabain at low concentrations also promoted cell proliferation in an ERK-dependent manner. These findings suggest that ouabain-stimulated ERK phosphorylation is required for Akt phosphorylation on Ser(473), cell proliferation, and stimulation of Na(+)/K(+)-ATPase-mediated (86)Rb uptake in OK cells.
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PMID:Ouabain stimulates protein kinase B (Akt) phosphorylation in opossum kidney proximal tubule cells through an ERK-dependent pathway. 1763 16