SIGNALMENT: (age, breed, sex, species, and scientific name)
Fifteen-week-old, male Zucker rats
TREATMENT PROTOCOL (including test compound):
11.25 mg/kg/day 2’ribose-modified phosphorothioate oligodeoxynucleotide adminstered subcutaneously daily for 46 days.
GROSS PATHOLOGY: None
LABORATORY RESULTS: (clinical pathology, microbiology, etc…)
MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY:
Renal tubular degeneration and basophilic granularity.
Treatment with a modified phosphorothioate oligodeoxynucleotide.
The renal alterations in these rats are typical of higher doses of oligodeoxynucleotides. The proximal convoluted tubules have degeneration characterized largely by reduced thickness of the brush border. Also, tubular epithelial cells have intracytoplasmic basophilic granules or inclusions. These are due to accumulation of the oligodeoxynucleotides within the cytoplasm and can be demonstrated as such with immunohistochemistry. Granules in the renal tubules are dose-dependent and disappearance of the granules and recovery is consistent with elimination or clearance of the oligonucleotide from the kidney. Ultrastructurally, basophilic granules include both membrane and nonmembrane bound electron dense material. The oligodeoxynucleotides adminstered to these rats did not result in alterations to clinical chemistry parameters. Slight effects on renal function (i.e., proteinuria and decrease GFR) have been noted with more severe histopathologic effects that have been reported previously (1).
The photomicrographs demonstrate typical renal alterations in rats given oligodeoxynucleotides. The alterations are a class effect of oligodeoxynucleotides and are unrelated to the sequence. The oligodeoxynucleotide administered to this rat had a nonsense sequence (predicted not to bind to rat mRNA) and served as a positive control for nonspecific oligodeoxynucleotide effects.
40X objective, HE, Normal renal cortex from saline treated control rat.
40X objective, HE, Renal cortex from a rat given the test compound.