Protection against gentamicin-induced early renal alterations (phospholipidosis and increased DNA synthesis) by coadministration of poly-L-aspartic acid.
Coadministration of polyaspartic acid protects against functional and pathological signs of gentamicin-induced nephrotoxicity in rats without reduction of drug accumulation in renal cortex (Williams et al., J. Pharmacol. Exp. Ther. 237: 919-925, 1986; Gilbert et al., J. Infect. Dis. 159: 945-953, 1989). We have assessed the influence of polyaspartic acid on the early alterations induced in kidney cortex by gentamicin, namely the lysosomal phospholipidosis and the increase in cell turnover. We used an infused rat model in which animals received a total dose of 100 mg/kg of gentamicin over 12 hr. Renal cortex was examined 2 hr (day 0) and 48 hr (day 2) after treatment. All animals received an injection of [3H]thymidine (200 microCi i.p.) before sacrifice. Coadministration of polyaspartic acid (drug-polypeptide mass ratio 1:2.5) did not modify the drug serum levels, as recorded during or shortly after the infusion. Yet, it was associated with 1) an increased (approximately 35%) drug cortical content at day 0; 2) a significant protection against both biochemical (decrease of sphingomyelinase activity at day 0; increase of lipid phosphorus content at day 2) and morphological (enlargement of lysosomes and deposition of myeloid bodies at day 2) signs of lysosomal phospholipidosis in proximal tubular cells; and 3) an almost complete protection against increased cell turnover (mostly in proximal tubules) in cortex at day 2, as assessed by the measurement of [3H]thymidine incorporation into DNA and the enumeration of S-phase cells after histoautoradiography. In addition, morphological studies revealed a larger number of apical vacuoles in proximal tubular cells of animals receiving polyaspartic acid alone (but not in combination with gentamicin), and the deposition of osmiophilic, homogenous material in the lysosomes of animals receiving the combination of gentamicin and polyaspartic acid. Together with the results reported in two companion papers (Kishore et al., J. Pharmacol. Exp. Ther. 867-874, and 875-885, 1990), these results provide evidence that protection afforded by polyaspartic acid extends to the earliest cellular alterations described in kidney for gentamicin, namely the lysosomal phospholipidosis, suggesting that this protecting agent exerts blocking effect from this step in the cascade of events relating drug cortical accumulation to renal toxicity.
Beauchamp
D
D
Laboratoire de Chimie Physiologique, Université Catholique de Louvain, Bruxelles, Belgium.
Laurent
G
G
Maldague
P
P
Abid
S
S
Kishore
B K
BK
Tulkens
P M
PM
D000818:Animals; D004247:DNA / Q000096:biosynthesis*; D005260:Female; D005839:Gentamicins / Q000378:metabolism / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000032:analysis; D014617:Vacuoles / Q000187:drug effects
D005839:Gentamicins; D010455:Peptides; D010743:Phospholipids; C017645:polyaspartate; D004247:DNA; D013108:Sphingomyelin Phosphodiesterase