Assessment of heavy metal nephrotoxicity in vitro using isolated rat glomeruli and proximal tubular fragments.
Nephrotoxic metals are thought to affect mainly the proximal tubule, but the pathophysiology of acute renal failure (ARF) caused by some of these compounds cannot be explained by damage to this part of the nephron alone. To compare toxic effects on different parts of the nephron, metabolic studies (de novo protein synthesis as assessed by amino acid incorporation and fatty acid oxidation) were performed in freshly isolated rat glomeruli and proximal tubular fragments (PTF) in the presence of increasing concentrations of mercury (Hg), chromium (Cr), and cadmium (Cd) salts. Glomerular protein synthesis was very sensitive to Hg (concentration to reduce protein synthesis by 50%: 3.4 microM) and Cr (15 microM), while in PTF amino acid incorporation was similarly affected by Cd and Hg (32 and 34 microM). Glomerular fatty acid synthesis was also more sensitive to Hg than that in PTF (3.2 vs 55 microM, p less than 0.005). In experiments to study the effects of reduced glutathione (0.5 and 1 mM) on the metal toxicity, preincubation of the fragments with reduced glutathione failed to protect glomeruli against subsequent exposure to the metals, but partially protected PTF (greater than 100 microM for Hg and Cd). These data show that isolated glomeruli are more susceptible to those metals with the potential to cause ARF in vivo, with Hg being the most potent toxin. The results suggest that the glomerular sensitivity to Hg may indicate an important target region of the nephron in the development of ARF which has previously not been recognized.