Comparative assessment of poly-L-aspartic and poly-L-glutamic acids as protectants against gentamicin-induced renal lysosomal phospholipidosis, phospholipiduria and cell proliferation in rats.
Coadministration of poly-L-aspartic acid (poly-L-Asp) protects rats against all measured signs of aminoglycoside nephrotoxicity. Based on in vitro and acute in vivo models, previously we hypothesized that poly-L-Asp protects by forming complexes with the drug in lysomes of proximal tubular cells. However, another closely related peptide, poly-L-glutamic acid (poly-L-Glu), could not protect against gentamicin-induced phospholipidosis and nephrotoxicity, presumably because it is susceptible to rapid hydrolysis in sysosomes in vivo. The present study expands the in vivo comparison between these two polyanions to a subacute model of rats and examines in detail the influence of these polymers on the qualitative and quantitative morphological alterations of lysosomes, phospholipiduria and proliferation of cortical cells induced by gentamicin. Our results not only demonstrated that despite a significantly higher drug cortical accumulation, the coadministration of poly-L-Asp almost completely protects against the development of all these early renal alteration but also pointed to the possibility of a mild, albeit apparently nonlethal, lysosomal thesaurismosis to develop under these conditions. In contrast, poly-L-Glu could not protect against these early renal alterations, though cortical drug accumulation was not significantly higher; however, it induced a conspicuous proliferation of peritubular interstitial cells. Therefore, the present work, taken together with the earlier results of ours as well as that of others, tends to strengthen the hypothesis that the site of action of poly-L-Asp must be in lysosomes, which are also the organelles that sequester and accumulate the drug.
Kishore
B K
BK
Laboratoire de Chimie Physiologique, Université Catholique de Louvain, Bruxelles, Belgium.
Ibrahim
S
S
Lambricht
P
P
Laurent
G
G
Maldague
P
P
Tulkens
P M
PM
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D005839:Gentamicins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007279:Injections, Subcutaneous; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects*; D010455:Peptides / Q000627:therapeutic use*; D010743:Phospholipids / Q000652:urine*; D011099:Polyglutamic Acid / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains
D005839:Gentamicins; D010455:Peptides; D010743:Phospholipids; D011099:Polyglutamic Acid; C017645:polyaspartate