Tissue from Fifteen-week-old, male Zucker Rats

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…) 

None 

MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY: 

Renal tubular degeneration and basophilic granularity.

Treatment with a modified phosphorothioate oligodeoxynucleotide.  

CONTRIBUTOR'S COMMENTS: 

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. 

REFERENCES: 

  1. Monteith DK, Horner MJ, Gillett NA, Butler M, Geary R, Burckin T, Ushiro-Watanabe T, Levin AA. 1999. Evaluation of the renal effects of an antisense phosphorothioate oligodeoxynucleotide in monkeys. Toxicol Pathol 27:307-17. 
  2. Monteith DK, Levin AA. 1999. Synthetic oligonucleotides: The development of antisense therapeutics. Toxicol Pathol 27:8-13. 
  3. Levin AA, Monteith DK, Leeds JM, Nicklin PL, Geary RS, Butler M, Templin MV, Henry SP. 1998. Toxicity of oligodeoxynucleotide therapeutic agents. In: Crooke ST, Ed. Antisense research and application. Vol. 131. Handbook of experimental pharmacology. Berlin: Springer-Verlag. p 169-215.

 

Image11.jpg

40X objective, HE, Normal renal cortex from saline treated control rat.

Image2.jpg

40X objective, HE, Renal cortex from a rat given the test compound.

 

1 Comment
1 Like

DDx LNA/Oligos

November 20, 2018 04:00 AM by Nadine Stokar-Regenscheit, DVM, DECVP

Accumulation of basophilic, granular material in prox. tubular epithelial cells. mild vacuolation and necrosis.

--> Accumulation of test compound or metabolite (i.e. seen with LNA/oligo nucleotides)

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