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Z Varghese

Publications and source records attributed to Z Varghese.

At least 37 records · Page 2Linked to original sources
PubMed1998

Differential ability of cells to promote oxidation of low density lipoproteins in vitro.

Atherosclerosis and focal segmental glomerulosclerosis share some common histological features and it is speculated that they result from similar pathobiological mechanisms. There is strong evidence that oxidation of low density lipoprotein (LDL) may be an initiating event in atherogenesis and that oxidised LDL may also be involved in the glomerulosclerotic process. In vitro studies have demonstrated that cells present in the arterial intima and kidney-derived cells promote LDL oxidation. The aim of this study was to compare LDL oxidation by kidney-derived human mesangial cells and proximal tubular cells, with human umbilical vein endothelial cells and the human monocyte cell line THP-1. We used the thiobarbituric acid assay and agarose gel electrophoresis to measure the extent of LDL oxidation. Our results demonstrate that all of the cell types used had the ability to oxidise LDL significantly more than cell-free controls and that endothelial cells induced the highest degree of oxidative modification of LDL under our experimental conditions.

Arteriosclerosis↗
PubMed1998

Cytokine regulation of low-density lipoprotein receptor gene transcription in human mesangial cells.

BACKGROUND: The intracellular transport of lipids through regulation of the LDL receptor (LDLr) may be important in the progression of renal dysfunction. The present study was undertaken to investigate whether cytokines have any major effects on LDLr regulation and lipid-mediated glomerular injury in human mesangial cells (HMC). METHODS: We explored the effects of 50 ng/ml of tumour necrosis factor alpha (TNF alpha), 5 ng/ml of transforming growth factor beta (TGF beta), platelet-derived growth factor (PDGF), and interleukin-1beta (IL-1beta) on the regulation of LDLr gene transcription in a human mesangial cell line (HMCL) using cell proliferation, LDL binding, northern blot and LDLr promoter activity assays. RESULTS: TNF alpha, TGF beta, PDGF or IL-1beta did not significantly stimulate HMCL proliferation at the concentrations given above, but maximally stimulated LDLr mRNA expression and increased LDLr promoter activity by 167.48+/-23.56%, 150.47+/-24.41%, 127.71+/-24.65% and 163.01+/-31.91% respectively, at 24 h. An increased LDL binding was observed in parallel with increased LDLr mRNA. The tyrosine kinase transduction pathway was involved in LDLr upregulation induced by all four cytokines. Additionally, TGF beta involved serine/threonine kinase and G-protein pathways, and IL-1beta involved calmodulin, serine/threonine kinase and PKC pathways in upregulating LDLr. A high concentration of LDL (250 microg/ml) inhibited promoter activity, but TNF alpha, TGF beta, PDGF and IL-1beta co-incubated with LDL could override transcriptional inhibition by LDL. CONCLUSION: TNF alpha, TGF beta, PDGF and IL-1beta increased LDLr gene expression by increasing sterol-independent and mitogenesis-independent gene transcription. This process may contribute to lipid deposition and foam cell formation in HMC.

Base Sequence↗
PubMed1997

Glomerular atherosclerosis.

This paper suggests a two-hit model for lipoprotein-mediated progressive renal disease, in which postsecretory modification of low-density lipoprotein may favour the transformation of mesangial cells, monocytes and macrophages to glomerular foam cells. Proteinuria and lipiduria would mediate tubulointerstitial damage. Based on this, careful treatment with lipid-lowering agents, lipopheresis and antioxidants may ameliorate the progression of glomerular and tubulointerstitial pathology.

Arteriosclerosis↗
PubMed1996

Do glomerular atherosclerosis and lipid-mediated tubulo-interstitial disease cause progressive renal failure in man?

The nephrotic syndrome presents the kidney with a new environment in which blood vessels, glomerular structures and tubules are exposed over substantial periods of time to lipoproteins. LDL has charge affinity with glomerular basement membrane glycosaminoglycans, so potentially increases or maintains albumin loss. This in turn stimulates LDL synthesis. HDL is small enough to be passed by the glomerular filter in substantial amounts and has been found to stimulate endothelin-1 production by human proximal tubular cells in culture. LDL also inhibits nitric oxide vasodilatory responses, an action which when added to that of endothelin-1 may result in decreased renal tissue oxygenation. Taken together, these aspects of the nephrotic syndrome broaden conventional definitions of atherosclerosis and offer a number of targets for therapy in progressive renal disease.

Arteriosclerosis↗
PubMed1993

Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria.

Experimental evidence suggests that lipid lowering therapy could slow the progression of renal disease in humans. We have conducted a double-blind, placebo controlled trial of the HMG CoA reductase inhibitor simvastatin in patients with the nephrotic syndrome or significant proteinuria (> 1 g/day) and hypercholesterolemia (> or = 6.5 mmol/liter). Patients were placed on a lipid lowering diet for at least 10 weeks before randomization. After a four-week placebo run-in, 30 adults were randomized to simvastatin or placebo therapy (10 mg/day, increasing to 20 to 40 mg/day as required) for 24 weeks. There were seven dropouts, none of whom were "definitely" related to drug therapy. Total and LDL cholesterol levels fell by a mean of 33 and 31%, respectively, in simvastatin treated patients, compared with only 5 and 1% in patients on placebo (P < 0.001, P = 0.002, respectively). Apolipoprotein B100 levels fell by a mean of 31% in the simvastatin group but rose 0.3% in the placebo group (P = 0.014). There were no significant changes in HDL levels. There were no significant differences between the groups in their urine protein levels, their rise in plasma creatinine, or decline in plasma inulin clearance. Simvastatin is a safe, effective therapy for hypercholesterolemia in proteinuric states. A much larger trial is needed to show if potent lipid-lowering therapy slows progression of hypercholesterolemic proteinuric diseases.

Adolescent↗
PubMed1993

Lipiduria in renal disease.

This article reviews the published data on lipiduria in both health and disease. Small amounts of lipid appear in the urine under normal circumstances but, in the nephrotic syndrome in humans, there is also a considerable amount of high-density lipoprotein in the urine as well as smaller amounts of other lipoproteins. Potential tubular re-uptake mechanisms for lipoproteins have been demonstrated in both animal and cell-culture models. In humans, there is no direct evidence for these specific re-uptake mechanisms--it is only through specific staining of renal biopsies for apolipoproteins that the presence of such mechanisms in intracellular vesicular structures is suggested. It is possible that lipoprotein filtration and re-uptake by the tubule are important mechanisms in tubular injury.

Animals↗
PubMed1993

Oxidation of low-density lipoproteins by rat mesangial cells and the interaction of oxidized low-density lipoproteins with rat mesangial cells in vitro.

Glomerulosclerosis and atherosclerosis share common pathobiological mechanisms. Experiments carried out in vitro over the past decade using cells thought to be involved in the atherosclerotic process such as endothelial cells, smooth muscle cells, and monocyte/macrophages have shown that postsecretory modifications such as oxidation increase the atherogenicity of LDL. Animal experiments employing antioxidant therapy have also been shown to slow the progression of atherosclerotic lesions. We set out to investigate the interactions between oxidized LDL (oxLDL) and rat mesangial cells (RMC) that might be of importance in the glomerulosclerotic process. Our results show that RMC have the ability to oxidize LDL, that oxLDL binding was 2-3-fold greater than native LDL (nLDL), and that oxLDL was more cytotoxic to these cells than nLDL. We speculate that cell-mediated oxidation of LDL in vivo may play a role in the progression of the glomerulosclerotic process.

Animals↗
PubMed1993

Effect of cyclosporin A on endothelin synthesis by cultured human renal cortical epithelial cells.

We report here for the first time that human renal proximal tubular cells secrete endothelin, clear evidence of de-novo endothelin synthesis by these cells and the effect of cyclosporin A (CsA) on endothelin synthesis both in short-term (24 h) and medium-term (5-day) culture. Human renal cortical epithelial cells were cultured and shown to possess proximal tubular characteristics. These cells produced endothelin in culture in a time-dependent manner, as measured by radioimmunoassay (291.6 +/- 51.4 pg/well/24 h). Furthermore, endothelin production by these cells was significantly decreased by up to 80% by cycloheximide (1051.8 +/- 54.9 pg/mg cell protein/24 h versus 253.2 +/- 12.6 pg/mg cell protein/24 h), showing that these cells actively synthesize endothelin. In short-term culture (24 h), CsA significantly inhibited endothelin synthesis at a medium concentration of 10,000 micrograms/l. No change in endothelin synthesis was seen at lower CsA concentrations. In contrast, over a 5-day period, a non-significant increase in endothelin synthesis was observed at CsA concentrations of 2000 micrograms/l (152.5 +/- 20.4%); however, cell growth was significantly decreased at this concentration (71.33 +/- 6.39%). Using a newly developed two-site immunoradiometric assay specific for endothelin-1 (ET-1), we demonstrate that ET-1 is the major endothelin isoform produced by human renal proximal tubular cells.

Animals↗
PubMed1993

Serum cholesterol falls spontaneously in nephrotic patients with progressive renal disease.

Total cholesterol (TC) levels were lower than expected in some patients with advanced renal disease and nephrotic-range proteinuria. Studies of 35 clinically stable nonuremic patients and of 12 nephrotic patients with advancing renal failure were therefore performed. Analysis of pooled biochemical data from 35 patients who were hypercholesterolemic on entry to the clinic revealed a positive correlation between TC and reciprocal creatinine (l/Cr) while serum albumin (ALB) was negatively correlated with l/Cr and TC. In the 12 nephrotic patients with negative reciprocal creatinine slopes there was a strong correlation between the slopes of l/Cr and TC. These data suggest that plasma cholesterol falls in the nephrotic hypercholesterolemic patients in whom renal disease progresses, and that the slopes of plasma cholesterol and reciprocal creatinine are closely related.

Cholesterol↗
PubMed1993

Low-dose simvastatin is safe in hyperlipidaemic renal transplant patients.

Hyperlipidaemia is common after renal transplantation, and because of its association with atherosclerosis, interest has increased in the use of lipid-lowering drugs in transplant patients. Dietary approaches have not been consistently successful, and multiple pharmacotherapy and drug interactions have led to difficulties in establishing lipid-lowering drug regimes. The statins reduce plasma cholesterol by inhibiting the rate-limiting step in cholesterol synthesis, and although some side-effects have been reported in their use after transplantation, the efficacy and safety of low doses has not been formally established. A randomized single-blind placebo crossover study designed to determine the safety and effectiveness of simvastatin in a single daily 5-mg evening dose was therefore conducted in 26 stable renal transplant patients, 14 of whom were receiving cyclosporin A. The results demonstrated no difference between total cholesterol levels in the baseline simvastatin and placebo periods: 7.97 +/- 1.2 and 7.59 +/- 1.5 mmol/l respectively. After 8 weeks of simvastatin, the total cholesterol declined significantly to 6.72 +/- 0.87 mmol/l (P < 0.001). A significant difference was found when the placebo and simvastatin cholesterol levels were compared at 4 and 8 weeks (P < 0.01). LDL cholesterol decreased from 4.74 +/- 0.87 to 3.78 +/- 0.78 mmol/l after 8 weeks on simvastatin (P < 0.001), and apo B fell from 142 +/- 31 to 112 +/- 22 mg/dl (P < 0.001). The difference in LDL cholesterol and apo B after 8 weeks of simvastatin when compared with the corresponding values on placebo was also significant (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Calcium set point progressively worsens in hemodialysis patients despite conventional oral 1-alpha hydroxycholecalciferol supplementation.

Calcium set point was measured in 12 patients on chronic hemodialysis. Dialysate calcium concentration was 1.65 mmol/l. Calcium carbonate (CaCO3) was used as the phosphate binder and oral 1-alpha hydroxycholecalciferol (alfacalcidol) was administered in a dose of 0.25-1.0 micrograms/day for 12 months. Comparing base line and post study values, there were no significant changes in ionized calcium (ICa++), intact immunoreactive parathyroid hormone (iPTH), plasma total calcium (TCa++), plasma phosphate (P), alkaline phosphatase (ALP), or aluminum (Al). However, the relative calcium set point significantly worsened (shifted to the right). Three patients developed hypercalcemia (25%) with a total calcium > 2.65 mmol/l. Total bone mineral content (BMC) fell suggesting demineralization. We conclude that this dose of oral alfacalcidol, CaCO3, and a dialysate calcium concentration of 1.65 mmol/l are not sufficient to halt the progression of secondary hyperparathyroidism in chronic hemodialysis patients. Measurement of calcium set point may be the best early measure of failure to prevent worsening of hyperparathyroidism.

Administration, Oral↗
PubMed1992

Lipoprotein(a) in patients with proteinuria.

Lipoprotein(a) (Lp(a)) has recently been recognized to be a risk factor for coronary heart disease. Lp(a) median values in the absence of renal disease are around 10 mg/dl. Higher levels (greater than or equal to 30 mg/dl) correlate with the occurrence of coronary heart disease, particularly in the presence of elevated cholesterol. We have studied Lp(a) in 76 adults with proteinuria. Fifty had glomerular diseases and 26 non-glomerular diseases, with renal function varying from normal to advanced chronic renal failure. Lp(a) values were shifted to the right, with a median of 21.0 mg/dl, and 25% of patients had values of 30 mg/dl or more. Lp(a) did not correlate with cholesterol, age, lipoprotein subclasses, apoproteins A-I or B-100, albumin, creatinine, or creatinine clearance. Median Lp(a) values did not differ significantly comparing men versus women, or glomerular versus non-glomerular disease. Lp(a) may inhibit fibrinolysis, and is deposited in atherosclerotic lesions. Although the cause of these elevated Lp(a) levels is uncertain, we propose that they contribute to the increased risk of coronary heart disease in the nephrotic syndrome, and may play a role in progressive renal disease.

Adolescent↗
PubMed1992

Effect of 24,25-dihydroxycholecalciferol on intestinal absorption of calcium and phosphate and on parathyroid hormone secretion in chronic renal failure.

Twelve patients with chronic renal failure (CRF) requiring dialysis, 7 of whom were hypercalcaemic, were treated with 24,25-dihydroxycholecalciferol [24,25(OH)2D3; 10 micrograms daily for 3 months] or placebo and the treatment then crossed over for a further 3 months. Treatment with 24,25(OH)2D3 was associated with small but significant increments in the fractional rates of absorption of calcium (p less than 0.01) and phosphate (p less than 0.05) measured by a combined radioisotope test, but even during treatment, the absorption of both calcium and phosphate remained subnormal. A significant fall in immunoreactive parathyroid hormone (i-PTH) levels occurred during treatment (p less than 0.05) in the absence of significant changes in plasma ionised calcium and plasma phosphate levels. In 7 patients, treatment with 24,25(OH)2D3 converted parathyroid glands which were non-suppressible by calcium infusion before treatment to suppressible ones (greater than 50% suppression of i-PTH levels) at similar levels of ionised calcium. 24,25(OH)2D3 may have a role in the treatment of renal osteodystrophy, especially in patients with hypercalcaemic hyperparathyroidism.

Adult↗
PubMed1991

Effects of dietary fatty acids in an animal model of focal glomerulosclerosis.

The obese Zucker rat develops hyperlipidemia, proteinuria and focal glomerulosclerosis without prior changes in renal hemodynamics. To study the effects of oral fatty acid intake on the development of renal injury in this model, rats were fed standard chow or chow supplemented with either 14% fish oil or 14% beef tallow after unilateral nephrectomy at the age of 10 weeks. At 32 weeks post-nephrectomy animals were sacrificed and renal tissue saved to assess histology and glomerular eicosanoid production. Fish-oil treated rats had lower mean plasma cholesterol levels and developed less proteinuria than control or tallow-fed animals although there was no difference in plasma creatinine or blood pressure. Histological analysis showed significantly fewer sclerosed glomeruli in the fish oil group (4.0 +/- 0.8% vs. control 19.4 +/- 4.1%, P less than 0.0005 and vs. beef tallow 10.8 +/- 1.9%, P less than 0.005). Glomeruli derived from rats on fish oil supplements produced smaller amounts of prostaglandin (PG)E2 and of the stable metabolites of PGI2 (6-oxo-PGF1 alpha), PGF2 (PGF2 alpha) and thromboxane (TX)A2 (TXB2) than those from tallow-fed animals. This study demonstrates that oral fatty acid intake may influence the development of glomerulosclerosis. The apparent beneficial effects of fish oil have not been fully defined, but may relate to favorable changes in plasma lipid concentration and renal eicosanoid production.

Animals↗
PubMed1991

Intraplatelet serotonin, beta-thromboglobulin, and histamine concentrations and thromboxane A2 synthesis in renal disease.

Intraplatelet serotonin (5-HT), beta-thromboglobulin (beta-TG), and histamine content as well as platelet total thromboxane A2 (TXA2) synthesizing capacity were measured in 53 patients with chronic renal disease: nephrotic syndrome (n = 18); end-stage renal failure (ESRF; n = 13); continuous ambulatory peritoneal dialysis (CAPD; n = 9); hemodialysis (HD; n = 13). These indices of platelet function were correlated with plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) concentrations. When compared with controls, intraplatelet 5-HT was significantly reduced in all patient groups studied and beta-TG was diminished in all patient groups except CAPD. Total platelet TXA2 synthesizing capacity was increased in ESRF and HD groups. Intraplatelet histamine content was not altered in any of the patient groups studied. There was a significant inverse correlation between intraplatelet 5-HT content on the one hand and plasma TC, LDL-C, and TG on the other. The depletion of intraplatelet 5-HT and beta-TG and the increase in total TXA2 synthesizing capacity are consistent with platelet activation in chronic renal disease. The correlation between these indices of platelet activation and TC, LDL-C, HDL-C, and TG suggests that changes in the concentrations of these lipids may contribute to the activation of platelets in these conditions.

Adolescent↗