摘要:

Aminoglycoside antibiotics are known to be transported and accumulated within lysosomes of renal proximal tubular cells and to cause proximal tubular cell injury and necrosis. The pathogenesis of aminoglycoside nephrotoxicity is postulated to be related to the capacity of these organic polycations to interact electrostatically with membrane anionic phospholipids and to disrupt membrane structure andfunction. Aminoglycoside antibiotics have been shown to bind to anionic phospholipids of model membranes and to alter membrane permeability and promote membrane aggregation. In vivo these drugs induce phospholipiduria and a renal cortical phospholipidosis. The latter reflects the accumulation of phospholipid-containing myeloid bodies within the lysosomal compartment consequent to aminoglycoside-induced inhibition of lysosomal phospholipases. The mechanism of drug-induced inhibition of phospholipases has been shown to be secondary to the binding of these cationic drugs to anionic phospholipids. As the lysosomes became progressively distended with myeloid bodies, they become unstable and eventually rupture, which results in the release of acid hydrolases as well as high concentrations of aminoglycosides into the cytoplasm where they interact with and disrupt the function of other membranes and organelles including mitochondria and microsomes. It is postulated that the redistribution of drug from the lysosomal compartment to organellar membranes is the critical event which triggers the irreversible injury cascade. Polyaspm'c acid is a polyanionic peptide which when administered in vitro or in vivo forms electrostatic complexes with aminoglycoside antibiotics and prevents these drugs from interacting with anionic phospholipia's, from perturbing phospholipid metabolism and from causing cell injury and necrosis.

ISSN:0886-022X    

DOI:10.3109/08860229209106642

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Alterations in membrane fluidity affect, via an effect on the ease with which proteins may change confonnation, the activity of various enzymes and transport systems. Recent experiments have shown that toxic injury is frequently associated with modijications in physical state and/or lipid composition ofphma membranes. Such modifications are likely to play a role in cell dysfunction, especially in epithelial cells whose optimal function depends on the polarity in membrane fluidity between apical and basolateral domains.

ISSN:0886-022X    

DOI:10.3109/08860229209106643

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

We have examined the role of reactive oxygen metabolites (ROM) in gentamicin nephrotoxicity and in glycerol-induced acute renal failure, a model for myoglobinuric acute renal failure. Several agents which affect mitochondrial respiration have been shown to enhance the generation of hydrogen peroxide. Based on gentamicin s ability to alter mitochondrial respiration both in vitro and in vivo we postulated that gentamicin may enhance the generation of ROM by renal com'cal mitochondria. Gentamicin, in a dose-dependent farhion, enhanced hydrogen peroxide production by rat renal cortical mitochondria as measured by the decrease in scopoletin jluorescence. At the highest concentration of gentamicin tested (4.0 mM), the rate of hydrogen peroxide generation w s markedly increased from 0. I7 f 0.02 to 6.21 f 0.67 nmol/mg/m*n. We next demonstrated that hydroxyl radical scavengers and an iron chelator provide a marked functional and histological protection in gentamicin-induced acute renal failure in rats. Hydroxyl radical scavengers and the iron chelator deferoxamine also protected renal function in glycerol-injected rats, a model for acute renal failure due to muscle injury. Although these data suggest that ROM may be important mediators of toxic renal injury, in vivo generation of ROM by kidney in normal and pathological states has not been previously examined. Aminotriazole (An irreversibly inactivates catalase only in the presence of hydrogen peroxide and previous studies have shown that AT-medated inhibition of catalase in a sensitive measure of in vivo changes in the hydrogen peroxide generation. Using this method, we have demonstrated the in vivo generation of hydrogen peroxide under normal conditions and enhanced generation of hydrogen peroxide in rats treated with gentamicin or glycerol. Finally, in in vitro studies we have shown that iron and intracellular calcium play a critical role in hydrogen peroxide-mediated cytotoxicity to LLC-PK, cells, a renal tubular epithelial cell line. Taken together our data provide evidence for a role of ROM in gentamicin and glycerol-induced acute renal failure and provide evidence for the role of iron and calcium in oxidant injury to renal tubular epithelial cells.

ISSN:0886-022X    

DOI:10.3109/08860229209106644

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

The characteristics of two established renal cell lines (LLC-PKI and OK) and of primary cultures of rabbit and human proximal tubule cells are described by summarizing the literature about speczjic properties retained by these cells in culture. Furthermore, comparative biochemical and functional properties are presented including both specijic marker enzymes and transport properties of these cells grown in various media. 7he impact of culture medium composition on the expressed cellular phenotype is discussed and its consequences on the projile of t o i c response due to aminoglycoside antibiotics is analyzed. The in vitro nephrotoxicity of three platinum-containing coordination complexes which exhibited different in vivo nephrotoxic potentials is studied by another technique in a model of rabbit proximal tubule cells in primary cultures in order to correlate results to in vivo data and to dejne reliable and sensitive parameters for the assessment of platinum-derivativeinduced nephrotoxicity. Although animal cell lines have been established in serumsupplemented madium, LLC-PK1 and OK cells as well as primary cultures of proximal tubules are successfully grown in hormonally dejined medium, the standardization of which is better controlled for nephrotoxicity studies.

ISSN:0886-022X    

DOI:10.3109/08860229209106645

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

ISSN:0886-022X    

DOI:10.3109/08860229209106646

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

ISSN:0886-022X    

DOI:10.3109/08860229209106647

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Acute glomemlonephritis can cause acute renal failure. Activated neutrophils and monocytes are major eflectors of glomerulonephritic renal failure. Adhesion molecules, granule enzymes, reactive oxygen radicals, lipid metabolites, and cytokines of activated neutrophils and monocytes mediate glomerular capillary constriction, occlusion, and destruction. Injurious products and biologically active mediators released by activated leukocytes have profound fictional eflects on mesangial cells and endothelial cells, which in turn participate in the disturbance of glomerularfinc-tion, for example, by altering capillary diameter and surface area. f i e glomerular injlammatory events result in decreased glomerular capillary ultrajiltraton coefl-cient and glomerular jiltration rate, as well as other functional perturbations.

ISSN:0886-022X    

DOI:10.3109/08860229209106648

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

ISSN:0886-022X    

DOI:10.3109/08860229209106649

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

Glomeruli possess a complex hemostasis system with prothrombotic (procoagulant, antifibrinolytic) and antithrombotic (anticoagulant, fibrinolytic) properties that can act locally on platelet adhesion or aggregation, on plasmatic coagulation pathways, and on fibrinolysis. In vitro, inflammatory mediators, such as XVF, favor glomerular thrombogenic properties through enhancement of thromboplastin synthesis and of plasminogen activator inhibitor PAI-1, and through decrease in thrombomdulin ac-tivity. In some diseases, intraglomerular Jibrin formation appears to be favored by increased glomerular prothrombotic properties, for example: augmented thromboplnstin activity in immune glomerulonephritides and in Shwartzman phenomenon, excessive thromboxane A2 synthesis, and decreased fibrinolytic activity in severe renal allografr rejection. In other diseases glomerular hemostasis appears to function homeostatically, for example, in thrombin-induced disseminated intravascular coagulation with enhancement offibrinolytic activity favoring fibrin dissolution. Novel methods allowing the study of glomerular hemostatic activities in renal biopsy fragments should help to understand the mechanisms of fibrin deposition in human diseases and to treat it on a logical basis.

ISSN:0886-022X    

DOI:10.3109/08860229209106650

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor

摘要:

The ACID truth and BASIC facts with a Sweet Touch, an enLYTEenment, by M. L. Halperin, Ross Mark Medical Publishers, Stirling, Ontario, Canada, 1991.

ISSN:0886-022X    

DOI:10.3109/08860229209106651

出版商:Taylor&Francis    

年代:1992

数据来源: Taylor