title: Spontaneously Occurring Formation of Intranuclear and Cytoplasmic Inclusions in Renal Proximal Epithelium Due to Accumulation of D-Amino Acid Oxidase in Wistar Hannover Rats.
abstract: Intranuclear and cytoplasmic inclusions in the renal proximal tubular epithelium were observed in nontreated male and female Wistar Hannover rats in a 26-week study (32 weeks of age) and a 104-week study (110 weeks of age). The incidence rates were less than 5% in these two studies. In affected animals, the inclusions were observed in more than 60% of proximal tubular epithelium as various sized (approximately 1-8 μm in diameter) round and eosinophilic materials, but not in distal tubules, Henle's loop, or collecting ducts. Ultrastructurally, inclusions appeared finely granular, homogenous with middle-electron density, and without a limiting membrane. These inclusions were determined to be protein histochemically stained by Azan-Mallory and immunoreactive with an antibody against D-amino acid oxidase (DAO). There was no abnormality in in-life observations or in clinical test values suggestive of renal dysfunction. There were no associated degenerative or inflammatory changes in the kidneys, and no similar inclusions were observed in the other organs. These inclusions are very similar to propiverine hydrochloride (propiverine) and norepinephreine/serotonin reuptake inhibitor-induced inclusions. This is the first report of accumulation of DAO and formation of inclusions occurring spontaneously in rat kidneys. The data are important for toxicological studies using Wistar Hannover rats.
authors.affiliation: Pathology Division, Gotemba Laboratories, BoZo Research Center Inc., Shizuoka, Japan shimoyama-natsumi@bozo.co.jp.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Shimoyama
authors.affiliation: Toxicologic Pathology, Drug Safety Research Laboratories, Astellas Pharma Inc., Osaka, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Nakatsuji
authors.affiliation: Pathology Division, Gotemba Laboratories, BoZo Research Center Inc., Shizuoka, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Andoh
authors.affiliation: Pathology Division, Gotemba Laboratories, BoZo Research Center Inc., Shizuoka, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Pathology Division, Gotemba Laboratories, BoZo Research Center Inc., Shizuoka, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Pathology Division, Gotemba Laboratories, BoZo Research Center Inc., Shizuoka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hoshiya
mesh_terms: D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000378:metabolism*; D004848:Epithelium / Q000201:enzymology / Q000473:pathology; D005260:Female; D002479:Inclusion Bodies / Q000201:enzymology* / Q000473:pathology; D045586:Intranuclear Inclusion Bodies / Q000201:enzymology / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003605:D-Amino-Acid Oxidase
keywords: Wistar Hannover rat; d-amino acid oxidase; intranuclear and cytoplasmic inclusions; proximal tubular epithelium