Kishore BK, Maldague P, Tulkens PM, Courtoy PJ
Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique de Louvain, Brussels, Belgium.
Renal damage caused by polycationic peptides is well documented, but
renal damage caused by polyanionic peptides is not. During our attempts
to inhibit the nephrotoxicity of aminoglycoside antibiotics by polyanionic
peptides, we discovered that poly-D-glutamic acid (molecular weight, 20
kd; 250 mg/kg/day subcutaneously for 1 to 4 days) produces an acute thesaurismosis
in the proximal tubular cells associated with a marked proliferation of
peritubular interstitial cells in rat kidney. Thesaurismotic bodies were
easily visualized by light microscopy at the basal pole of proximal tubular
cells with the cationic stain Giemsa. By electron microscopy, these bodies
appeared membrane-limited, frequently distorted, filled with heterogeneous
granular material, accessible to injected peroxidase (a tracer of the endocytic
pathway), and generally stainable for the lysosomal enzyme arylsulfatase.
Specimens obtained 3 hours after injection of poly-D-glutamic acid and
horseradish peroxidase suggested an impairment of endosome and/or lysosome
fission, but not fusion. By histoautoradiographic examination after 3H-thymidine
incorporation, global labeling indices of cortical cells were increased
11- to 18-fold in poly-D-glutamic acid-treated rats as compared with controls,
with > 80% of labeled cells localized in the interstitium. Distal
tubular and glomerular cells also showed a moderate proliferation, but
proximal tubular cells showed no significant necrosis or proliferation.
Although tubular thesaurismosis persisted, interstitial cell proliferation
resolved within 7 days after cessation of treatment. We suggest that poly-D-glutamic
acid is a convenient tool to induce a rapid and sustained lysosomal storage
disorder. It could also help clarify the relationship between insults to
tubular cells and proliferation of peritubular cells, two features frequently
associated in tubulointerstitial disorders. The mechanism of the thesaurismosis
and of the interference with the dynamics of fusion-fission of the endocytic
apparatus are addressed in the companion paper.
PMID: 8667606, UI: 96249110