Nephrotoxicity: A rational approach to target cell injury in vitro in the kidney

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 hexa-chlorobutadiene 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.