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Biomedical subjects

A Heidland

Publications and source records attributed to A Heidland.

At least 55 records · Page 3Linked to original sources
PubMed1999

Increased genomic damage in lymphocytes of patients before and after long-term maintenance hemodialysis therapy.

This study investigates spontaneous genomic damage in peripheral lymphocytes of 19 patients with severe end-stage renal disease not enrolled onto a maintenance hemodialysis (MHD) program (creatinine level, 5.4 to 10.5 mg/dL) and 16 long-term MHD patients (111 to 282 months on MHD) and the possible association of genomic damage with the degree of renal insufficiency and duration of MHD. Genomic damage was assessed by evaluating the numbers of micronuclei (MN), which are cytoplasmic DNA-containing structures. The average number of MN in the control group of 23 healthy subjects was 15.3 +/- 4.7 MN/1,000 binucleate (BN) cells. The MN frequencies in the long-term MHD group were significantly greater (44.3 +/- 13.7 MN/1,000 BN) than the control frequencies. A significant increase in MN frequencies (28.2 +/- 9.4 MN/1,000 BN) was also seen in patients with advanced renal failure. The major findings of the study, high MN frequencies in long-term hemodialysis and advanced chronic renal failure patients, may result from decreased DNA repair previously shown and may contribute to the increased cancer incidence in these patients.

Adult↗
PubMed1999

Efficiency of 1-year treatment with fluvastatin in hyperlipidemic patients with nephrotic syndrome.

The influence of fluvastatin, a liver-selective, competitive inhibitor of the 3-hydroxymethyl-glutaryl-coenzyme A reductase, on the lipoprotein metabolism was investigated in 9 patients with nephrotic syndrome. All patients had biopsy-proven renal disease as cause of their nephrotic syndrome and exhibited severe hyperlipidemia [baseline: serum cholesterol 358 +/- 46 mg/dl (9.3 mmol/l), low-density lipoprotein cholesterol 236 +/- 18 mg/dl (6.1 mmol/l), triglycerides 333 +/- 28 mg/dl (3.8 mmol/l), and lipoprotein Lp(a) 46 +/- 11 mg/dl]. After 1 year of 40 mg of fluvastatin, significant reductions of total cholesterol by 31% to 242 +/- 26 mg/dl (6.3 mmol/l) and low-density lipoprotein cholesterol by 29% to 162 +/- 12 mg/dl (4.2 mmol/l) were observed. Furthermore, triglyceride values were also lowered significantly by 19% to 268 +/- 21 mg/dl (3.1 mmol/l). Lipoprotein Lp(a) and high-density lipoprotein-cholesterol remained unchanged by fluvastatin. These improvements in lipid profile were maintained during the entire follow-up period of 1 year. There were no adverse events, and the slight increase in serum creatinine observed during the study was considered to be due to the primary renal disease. In conclusion, long- term administration of fluvastatin in patients with nephrotic syndrome appears to be an effective and safe treatment of the hyperlipidemia associated with this disorder.

Adult↗
PubMed1999

Suppressed activities of cathepsins and metalloproteinases in the chronic model of puromycin aminonucleoside nephrosis.

Glomerulosclerosis and tubulointerstitial fibrosis are the hallmarks of chronic renal diseases. In the present study, we have investigated the potential involvement of various proteinases in these alterations in the model of puromycin aminonucleoside (PAN) nephrosis. Two groups of male Wistar rats were given either three or seven injections of PAN (2.0 mg/100 g body weight) over a 4- and 12-week period, respectively. The two control groups received saline injections. Activities of cathepsins (B, H and L) were determined in isolated glomeruli and proximal tubules. Moreover, collagenase-like and gelatinase-like activities were analyzed in isolated glomeruli. Three weeks after weekly PAN injection, the rats developed heavy proteinuria (140.8+/-22.0 vs. 13.5+/-3.29 mg/day; p<0.001), and at week 11 protein excretion reached 606.6+/-23.00 vs. 22.8+/-1.5 mg/day. Renal morphology revealed minimal glomerular mesangial changes at the 4th week after PAN administration. At the 12th week a marked mesangial matrix accumulation as well as severe tubulointerstitial infiltration and fibrosis associated with tubular dilation and atrophy were observed. Glomerular cathepsins B, H, and L and gelatinase-like activities decreased at the 4th week after the first PAN injection and remained at this low level throughout the entire study period. Glomerular collagenase-like activity decreased at the 4th week (p<0.05) and was still mildly lower than that of the control group at the 12th week, but without significance. In the isolated proximal tubules, the activities of cathepsins B, H, and L showed the same pattern of decreases as those found in the glomeruli over the whole experimental period. Taken together, our data in the model of chronic PAN nephrosis suggest that the suppressed activities of cathepsins as well as the decreased gelatinase- and collagenase-like activities participate in the accumulation of extracellular matrix and thereby may contribute to the development of glomerulosclerosis and tubulointerstitial fibrosis.

Animals↗
PubMed1998

Mesangial cell hypertrophy induced by NH4Cl: role of depressed activities of cathepsins due to elevated lysosomal pH.

Enhanced ammoniagenesis is currently thought to play an important role in renal hypertrophy and subsequent tubulointerstitial fibrosis. Under certain conditions glomeruli also may be affected by ammonia toxicity. Exposure of glomeruli to augmented ammonia levels may occur: (i) in advanced liver diseases due to elevated blood ammonia concentrations; (ii) in conditions of enhanced tubular ammoniagenesis following cortical "trapping;" and (iii) due to increased ammonia formation in the glomeruli in the presence of impaired renal function. To elucidate the potential role of ammonia in glomerular injury, we investigated the effect of NH4Cl on protein turnover as well as on activities of various cathepsins in cultured rat mesangial cells. The results show that NH4Cl (20 mM) induced cell hypertrophy as defined by an increase in both cell protein content and cell volume (+38% and +10.1%, respectively, after 48 hr). This hypertrophy was associated with suppression of the activities of cathepsins B and L + B (-56.8% and -51.3% after 48 hr) and reduction of protein degradation rate (-61% after 48 hr), but without enhanced protein synthesis. Inhibition of Na+/H+ antiport by amiloride (1 mM) neither prevented the reduction of cathepsin activities nor the hypertrophy of the mesangial cells. Upon NH4Cl application lysosomal pH was elevated. This alkalinization may be causatively involved in the impairment of cathepsin B and L + B due to shifting the lysosomal pH above the optimum of their activities. In conclusion, NH4Cl induces hypertrophy but not hyperplasia in mesangial cells. This hypertrophy is caused by the reduction of protein degradation, mainly due to depressed activities of cathepsin B and L + B in the absence of enhanced protein synthesis. A shift of lysosomal pH above the optimum of the acidic cathepsins seems to be a key factor in their impaired activities in mesangial cells.

Ammonium Chloride↗
PubMed1998

Mechanisms and clinical significance of cell volume regulation.

A wide variety of factors challenge constancy of cell volume. Alterations of cell volume activate diverse cell volume regulatory mechanisms including ion transport, osmolyte accumulation, metabolism and expression of appropriate genes. A wealth of cellular signalling pathways link cell volume to the respective regulatory mechanisms. Cell volume emerges as a pathophysiologically important parameter in several diseases including diabetes mellitus, uraemia, hepatic insufficiency and hypercatabolic states. The role of altered cell volume in disease is a challenge which requires more experimental research and clinical investigation.

Animals↗
PubMed1998

Cancer in end-stage renal disease: potential factors involved -editorial-.

Increased incidence of cancer at various sites is observed in patients with end-stage renal disease (ESRD). In particular, lymphomas and carcinomas of the kidney, prostate, liver and uterus show an enhanced prevalence in these subjects compared with the general population. A multitude of factors directly or indirectly associated with the renal disease and the treatment regimens may contribute to the increased tumor formation in these patients. Impaired function of the immune system and of DNA repair mechanisms as well as reduced antioxidant defense, accumulation of carcinogenic compounds partly due to reduced renal elimination as well as chronic infections and inflammations are found more frequently in patients with ESRD compared with the general population and may act in concert to accelerate malignant transformation and tumor formation.

Humans↗
PubMed1998

Effect of chronic therapy with proteolytic enzymes on hypertension-induced renal injury in the rat model of Goldblatt hypertension.

This study investigated the possible beneficial effect of intraperitoneal proteolytic enzyme administration on the development of hypertension-induced renal injury in the rat model of 2-kidney 1-clip (2K1C) Goldblatt hypertension. Male Wistar rats (120-150 g) underwent either sham surgery (control, n = 5) or clipping of the left renal artery. From day one 2K1C rats were randomized into 2 groups, placebo treatment (n = 7), and proteolytic enzyme treatment (n = 9). To the verum group a fixed mixture of trypsin (2.42 mg), bromelain (4.54 mg), and rutin (5.04 mg) dissolved in 2 ml of sterile 0.9% NaCl was administered intraperitoneally daily, while the placebo group received only vehicle. Rats were pair-fed. The duration of the study was 7 weeks. All 2K1C rats developed hypertension and the mean values of systolic blood pressure (SBP) did not differ significantly between the groups at any time recorded (SBP at sacrifice: controls 122.0 +/- 8.5 mm Hg; placebo 191.4 +/- 7. 6 mm Hg; enzyme 180.5 +/- 6.5 mm Hg). Enzyme treatment prevented the rise in proteinuria (controls 12.4 +/- 2.6 mg/24 h; placebo 19.7 +/- 3.9 mg/24 h; enzyme 12.2 +/- 1.3 mg/24 h; p < 0.05) and ameliorated the increase in serum urea concentrations. Histomorphologically, signs of malignant nephrosclerosis were not found in control rats, while they were present in 4/7 (57%) of placebo-treated rats, but only in 1/9 (11%) of the enzyme-treated group. The volume fraction of renocortical interstitium was increased in both 2K1C groups in comparison with controls; however, enzyme treatment decreased the accumulation of interstitial tissue significantly (-22%) compared to placebo treatment. Cellular infiltration with mononuclear cells was also lower in the protease-treated group. To summarize, in the rat model of 2K1C hypertension, systemic treatment with proteases ameliorates the severity of nephrosclerosis and tubulointerstitial fibrosis in the non-clipped kidney, as well as proteinuria, without affecting high blood pressure.

Animals↗
PubMed1998

High-glucose media enhance the responsiveness of tubular cells to growth promoters: effect on lysosomal cathepsins and protein degradation.

Nephromegaly is a prominent feature of diabetic nephropathy and predominantly reflects increased renal tubule mass, mostly due to hypertrophy. To elucidate pathogenetic factors involved, we studied the effects of high glucose (HG) alone, and in combination with hormones/growth promoters: angiotensin II (10(-7) M); parathyroid hormone (10(-7) M); insulin-like growth factor-1 (10(-7) M), or transforming growth factor-beta1 (TGF-beta1, 10 ng/ml) in a renal cell line (LLC-PK1) with many characteristics of the proximal tubule. Activities of lysosomal cathepsins (B, L+B and H) and the protein turnover were investigated. Exposure to HG (25 mM) for up to 48 h increased cellular protein content, due to enhanced protein synthesis, while protein degradation rate and cathepsin activities tended to lower values. Hyperosmotic mechanisms of glucose action were excluded, since these effects were not induced by mannitol. In normoglycemic conditions only TGF-beta1 decreased cathepsin activities and protein degradation rate significantly. However, in HG media all applied hormones/growth factors significantly lowered the protein degradation rate, as well as lysosomal cathepsin activities. The enhanced responsiveness could contribute to the impaired protein turnover, with consequent hypertrophy of the tubulointerstitium in diabetic nephropathy.

Angiotensin II↗
PubMed1998

Alcohol abuse: potential role in electrolyte disturbances and kidney diseases.

The present review summarizes the current knowledge on the multiple effects of alcohol overconsumption on the kidney function as well as on water, electrolyte and acid-base homeostasis. In contrast to the well known transitory diuretic effects, the overall long-term effect of chronic alcohol overconsumption is water and salt retention with expansion of extracellular volume. Furthermore, depletion of magnesium, phosphate and calcium is also frequently found in alcohol-dependent patients. These electrolyte disturbances may be associated with the alcohol-induced hypoparathyroidism and parathyroid hormone resistance of the skeletal muscle as well as with the decrease of serum osteocalcin. Metabolic acidosis with lower arterial blood pH and plasma bicarbonate concentrations was revealed in alcoholic patients upon admission and a significant correlation between chronic alcohol overconsumption and increased incidence of hyperuricemia and gout attacks was also reported. Alcohol seems to have dual effects on the blood pressure. Increased blood pressure was demonstrated in men above 80 g and in women above 40 g ethanol consumption daily. In contrast, young adults consuming only 10 to 20 g per day had lower blood pressure than the abstinent group indicating a J-curve relationship. This is in line with the lowered risk for coronary heart disease associated with regular consumption of small alcohol amounts. The mechanisms responsible for the association between alcohol overconsumption and postinfectious glomerulonephritis have not been elucidated yet. Finally severe alcohol abuse predisposes to acute renal failure and seems to be associated with the general catabolic effects.

Acute Kidney Injury↗
PubMed1998

Advanced glycated albumin impairs protein degradation in the kidney proximal tubules cell line LLC-PK1.

Advanced glycation end-products (AGEs) are assumed to play a major role in the genesis of diabetic nephropathy and other diabetic complications. We studied the potential effect of AGEs on protein turnover and lysosomal proteinase activities in LLC-PK1 cells, a pig kidney proximal tubules cell line. Advanced glycated bovine serum albumin (AGE-BSA) was used as a model of AGEs and its action was compared to that of nonglycated BSA. AGE-BSA but not BSA (50 micromol/l) induced a significant increase in cell volume (BSA: 4870.6 +/- 74.8 fl, AGE-BSA: 5718.0 +/- 20.7 fl, p<0.01). Protein degradation rate was decreased by 13.8% after 48 hrs. incubation with AGE-BSA (p<0.01) while protein synthesis increased by 19,1%, (p<0.01). After incubation with AGE-BSA but not BSA activities of lysosomal cathepsins (B, L+B and H) decreased in a time- and dose-dependent fashion. This decline was neither caused by a shift in lysosomal pH outside the optimal range for cathepsins, nor by a direct inhibitory effect of AGEs modified proteins or peptides but most probably by inhibition of cathepsin B expression as measured by RT-PCR. It is supposed that impaired protease activities participated in decreased protein breakdown and cell enlargement. For the first time our data provide the evidence that AGEs induce hypertrophy of LLC-PK1 cells due to decreased protein breakdown resulting from reduced lysosomal proteinase activities with a concomitant stimulation of protein synthesis.

Animals↗
PubMed1997

Advanced glycation endproducts stimulate the MAP-kinase pathway in tubulus cell line LLC-PK1.

Advanced glycation endproducts (AGEs) are suggested to play an important role in diabetic nephropathy. They induce specific cellular responses such as the release of cytokines in different cell lines. The effect of AGEs on signal transduction pathways was investigated in the renal tubulus cell line LLC-PK1. Using a serine-phosphate-specific antibody AGE-induced cellular responses associated with phosphorylation/dephosphorylation events were demonstrated. In particular, the p42MAP kinase and its downstream target, the AP-1 complex, are shown to be activated by AGE-BSA but not by BSA. In contrast, only partial phosphorylation is observed for the p70S6-kinase. Thus, AGEs appear to induce specific signal transduction pathways.

Animals↗
PubMed1997

[Increased cancer incidence in terminal kidney failure: potential pathogenetic mechanisms].

Increased incidence of cancer in various sites is observed in patients with end-stage renal disease. A multitude of carcinogenic factors directly or indirectly associated with the disease may be involved. Impaired function of the immune system as well as impaired antioxidant defence, accumulation of carcinogenic compounds partly due to impaired renal elimination, and chronic infection and inflammation are found with increased prevalence in these patients and may contribute to enhanced tumor formation. Furthermore, factors associated with the dialysis treatment, such as bio-incompatibility reactions due to complement activating membranes, immunosuppressive medication in the course of prior unsuccessful renal transplantation, and impairment of DNA repair may also act in concert to accelerate malignant transformation.

Antioxidants↗
PubMed1997

Determination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA.

Recent studies suggest that advanced glycation endproducts play an important role in cardiovascular complications of ageing, diabetes and end-stage renal failure. Since highly elevated levels of advanced glycation endproducts are present in serum of patients on maintenance haemodialysis, an accurate and rapid assay for their determination would be useful. This would be particularly valuable for monitoring the removal of advanced glycation endproducts by novel dialysis membranes, as well as the effect of new drugs for the inhibition of their formation. Measurement of advanced glycation endproducts in serum was performed by two competitive ELISAs, using a monoclonal antibody directed against imidazolone, an advanced glycation endproduct formed by the reaction of arginine with 3-deoxyglucosone, and a polyclonal antibody directed against keyhole limpet haemocyanin-advanced glycation endproduct, as well as by quantitative fluorescence spectroscopy. Each of the assays showed significant differences between the controls and the maintenance haemodialysis patients. Advanced glycation endproduct levels determined by each of the ELISAs correlated with total and protein-bound fluorescence, but not with each other, suggesting a variable distribution of advanced glycation endproducts on serum proteins among the maintenance haemodialysis patients.

Aged↗
PubMed1997

Effect of cellular hydration on protein metabolism.

In the past few years, the paramount importance of cell volume for the regulation of cell function, including protein metabolism, has been recognized. Among many other effects, cell swelling inhibits proteolysis and stimulates protein synthesis, whereas cell shrinkage stimulates proteolysis and inhibits protein synthesis. Moreover, cell swelling and cell shrinkage influence the expression of a number of genes, including carriers, enzymes, and signaling molecules. Hormones exploit the influence of cell volume on metabolism to exert their effects. Insulin swells hepatocytes by activation of Na-/H+ exchange and Na+,K+,2Cl- cotransport, while glucagon shrinks hepatocytes by activation of ion channels. The effects of these hormones on hepatic proteolysis completely depend on their influence on cell volume. The effects of cell volume are mediated in part by alterations of lysosomal pH, which modifies the activity of acidic lysosomal proteases. Transforming growth factor-beta 1, as other growth factors, activates the Na+/H+ exchanger, swells cells, leads to lysosomal alkalinization, inhibits proteolysis and may thus contribute to renal hypertrophy in chronic renal disease. Moreover, a decrease in cell volume correlates with catabolic states in a variety of diseases.

Animals↗