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Nephrotoxicity: a rational approach to target cell injury in vitro in the kidney
1Robens Institute of Industrial and Environmental Health and Safety, University of Surrey, Guildford, UK.
Abstract:
1. The kidney is a complex organ in which there is cellular heterogeneity. Many nephrotoxic chemicals target preferentially for discrete cell types, but adjacent, morphologically different cells are unaffected. This selectivity has made the assessment of nephrotoxicity in vivo (and the study of underlying mechanisms) difficult. Discrete renal injury can, however, be exploited in vitro, to study the interactions between the toxic compound and the target cell. 2. Several in vitro models have been used to study the potential interaction between the target cells and chemicals, including perfusion of the isolated kidney, renal slices, freshly isolated fragments, primary cultures and continuous cell lines. Where appropriate, isolated organelles and purified enzymes can also be used. 3. The target cell toxicity in vivo of adriamycin, 2-bromoethanamine and hexachlorobutadiene N-acetyl cysteine conjugate is selectively maintained towards glomerular epithelial, medullary interstitial and proximal tubular cells, respectively, in vitro, showing that the "in vivo-in vitro gap" can be bridged. Characteristics unique to each of these renal cell types, such as the selective uptake of a toxin, enzyme systems for generating biologically reactive intermediates, and the presence of lipid droplets (rich in polyunsaturated fatty acid) and peroxidase activity have been identified, and one or more of these may explain the mechanisms of selective injury in discrete regions of the kidney.
Insights
Bridging the in vivo-in vitro gap in nephrotoxicity studies is possible. Specific kidney cell types maintain their unique toxic responses in vitro, aiding mechanism discovery.
Area of Science:
- Nephrology
- Toxicology
- Cell Biology
Background:
- Kidney exhibits cellular heterogeneity, complicating nephrotoxicity assessment.
- Nephrotoxic chemicals often target specific cell types, leaving others unaffected.
- Understanding selective renal injury mechanisms requires effective in vitro models.
Purpose of the Study:
- To demonstrate that in vitro models can bridge the in vivo-in vitro gap for nephrotoxicity.
- To identify mechanisms underlying selective chemical injury in distinct kidney cell types.
Main Methods:
- Utilized various in vitro models: isolated perfused kidney, renal slices, primary cultures, and cell lines.
- Examined selective toxicity of adriamycin, 2-bromoethanamine, and a hexachlorobutadiene metabolite.
- Investigated unique cellular characteristics like toxin uptake, enzyme activity, and lipid content.
Main Results:
- In vitro models successfully replicated in vivo selective toxicity towards specific renal cells (glomerular epithelial, medullary interstitial, proximal tubular).
- Identified unique cellular features contributing to selective injury, including selective toxin uptake and specific enzyme systems.
- Highlighted the role of lipid droplets and peroxidase activity in mediating regional kidney injury.
Conclusions:
- In vitro models are valuable tools for studying selective nephrotoxicity and bridging the in vivo-in vitro gap.
- Cell-specific characteristics are key determinants of differential chemical toxicity within the kidney.
- This approach facilitates the elucidation of mechanisms underlying discrete renal injury.