Abstract
In a previously published report we detailed an in situ method to quantify cell death in the renal cortex by perfusing the cell membrane impermeable fluorochrome, ethidium homodimer in situ. The objective of the present study was to use this in situ viability assay to examine cell death following the administration of nephrotoxic drugs known to produce cell death and/or injury in specific segments of the nephron. Male Sprague/Dawley rats were treated with the following nephrotoxicants: Gentamicin, amphotericin-B, and indomethacin. Results of the in situ viability assay indicated that gentamicin and amphotericin-B treatment caused cell death localized in the kidney cortex and medulla, respectively. The urinary biomarker kidney injury molecule—1 (Kim-1) showed significant increases in both gentamicin (20 fold increase) and amphotericin-B-treated (9.2 fold increase) animals. Urinary alpha glutathione-S-transferase (GST) showed significant increases for gentamicin (6.2 fold increase) only and mu GST for amphotericin-B-treated (19.1 fold increase) animals only. These results show that this in situ viability assay provides a sensitive method to identify cell death in different regions of the kidney. Furthermore, urinary alpha GST and mu GST are specific for proximal and distal tubule injury, respectively; urinary Kim-1 demonstrated greater sensitivity to both proximal and distal tubule injury.
Highlights
Drug-induced nephrotoxicity is common and occurs in 19% to 26% of hospitalized patients [1,2]
As part of our ongoing research to identify the mechanisms by which the environmental toxicant, cadmium, produces its nephrotoxic effects we have developed a method to assess changes in cell viability in the renal cortex
The objective of the present study was to compare the ability of site-specific urinary biomarkers of renal injury to a viability assay utilizing an in situ perfusion to detect changes in renal cell viability
Summary
Drug-induced nephrotoxicity is common and occurs in 19% to 26% of hospitalized patients [1,2]. Detection of drug-induced nephrotoxicity is critical as the effect may be reversed if the administration of the offending agent is stopped quickly enough. The use of urinary biomarkers to detect early-stage nephrotoxicity is an important aspect of general practice medicine, preclinical drug safety testing and workplace monitoring programs [4]. While the presence of some of these biomarkers in urine is not necessarily due to renal damage, there are urinary biomarkers that purportedly indicate specific sites of nephrotoxic injury. Biomarkers such as kidney injury molecule-one (Kim-1) [5] and alpha glutathione S-transferase (GST) are elevated in urine when proximal tubules become damaged or injured. In contrast to the use of non-invasive serum or urinary biomarkers to determine renal injury, more traditional methods involve the histological examination of renal tissue to detect cell death or injury
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