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Gentamicin nephrotoxicity in rats. I. Acute biochemical and ultrastructural effects
Abstract:
This investigation characterizes the acute biochemical and ultrastructural alterations within the rat kidney following the single injection of 10, 40, 80, or 160 mg. of gentamicin per kilogram of rat weight. Gentamicin was given intraperitoneally and rats were killed 80 minutes later. To assess a possible inhibitory effect upon protein synthesis 3H-leucine was injected 20 minutes postantibiotic and renal cortex was assayed for whole tissue and the protein fraction amino acid uptake. To exclude the possibility of gentamicin-induced lysosomal membrane instability with subsequent release of acid hydrolases, the activity of acid phosphatase was assayed in the supernatant and the residue of cortical homogenates containing the lysosomal fraction. Ultrastructural changes were concomitantly studied. To determine the intracellular localization of gentamicin, levels of the antibiotic were measured in subcellular fractions of cortical homogenates obtained from rats 2 hours following a single subcutaneous injection of 20 mg. of gentamicin per kilogram of rat weight. No gentamicin-induced alterations either of protein synthesis or of acid phosphatase distribution were demonstrated. Ultrastructural changes were most marked at 160 mg. per kg. consisting mainly of dilation of the endoplasmic reticulum, altered mitochondria, and increased cytosegresomes. Significant quantities of gentamicin were distributed within the nuclear, mitochondrial, and microsomal fractions. These studies indicate that although cytoplasmic alterations are prominent within the proximal tubular epithelial cells, they are not likely the result of either inhibition of protein synthesis or release of acid phosphatase from lysosomes.
Insights
Gentamicin causes kidney cell damage, including endoplasmic reticulum dilation and mitochondrial changes, particularly at higher doses. These acute effects are not due to inhibited protein synthesis or lysosomal enzyme release.
Area of Science:
- Nephrology
- Toxicology
- Cell Biology
Background:
- Gentamicin is a widely used antibiotic with known nephrotoxic potential.
- The precise mechanisms underlying gentamicin-induced kidney injury remain incompletely understood.
- Acute cellular alterations in the rat kidney following gentamicin exposure require detailed characterization.
Purpose of the Study:
- To investigate the acute biochemical and ultrastructural changes in rat kidneys after gentamicin administration.
- To assess the potential role of protein synthesis inhibition and lysosomal instability in gentamicin nephrotoxicity.
- To determine the intracellular localization of gentamicin within renal cortical cells.
Main Methods:
- Rats received single intraperitoneal injections of gentamicin (10-160 mg/kg) and were euthanized after 80 minutes.
- Protein synthesis was evaluated using 3H-leucine uptake in renal cortex.
- Lysosomal integrity was assessed by measuring acid phosphatase activity in cortical homogenates.
- Ultrastructural changes were examined via electron microscopy.
- Intracellular gentamicin distribution was quantified in subcellular fractions.
Main Results:
- No significant inhibition of protein synthesis or alteration in acid phosphatase distribution was observed.
- Marked ultrastructural changes, including endoplasmic reticulum dilation, mitochondrial alterations, and increased cytosegresomes, were noted at 160 mg/kg.
- Significant gentamicin accumulation was found in nuclear, mitochondrial, and microsomal fractions.
- Acute cytoplasmic alterations in proximal tubular cells were prominent.
Conclusions:
- The acute nephrotoxic effects of gentamicin in rats are characterized by prominent cytoplasmic ultrastructural changes.
- These changes are unlikely to be caused by direct inhibition of protein synthesis or by lysosomal membrane instability.
- Gentamicin distributes to various subcellular compartments within renal tubular cells, suggesting complex mechanisms of toxicity.