Proliferative and Nonproliferative Lesions of the Rat and Mouse Urinary System

Abstract

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in the urinary tract of rats and mice. The standardized nomenclature of urinary tract lesions presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as those induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for urinary tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

“…60 h (Cappelletti et al 2013);α2u-globulin: approx. 6 h (Lehman-McKeeman et al 1990)), whereby binding of chemicals to α2u-globulin extends this half-life markedly and exacerbates the accumulation of α2u-globulin in the lysosomes of exposed male rats (Swenberg et al 1989;Lehman-McKeeman et al 1990;Frazier et al 2012). Consequently, we investigated whether propiverine interacts with DAAO in vitro, thus resulting in the cytosolic and nuclear DAAO accumulations observed in vivo.…”

“…This nephropathy is characterized by the renal proximal tubule epithelial accumulation of α2-urinary globulin, a fatty acid-binding protein synthesized exclusively in the liver of male rats and reabsorbed in the renal proximal tubules. The accumulation of α2u-globulin is governed by the reversible binding of compounds or their metabolites, resulting in slower enzymatic degradation of α2u-globulin (Swenberg et al 1989;Lehman-McKeeman et al 1990;Frazier et al 2012). Of note, the analogous mouse urinary protein (MUP) does not bind the α2u-binding compounds nor does it accumulate in the renal proximal tubules of mice (Dietrich and Rasonyi 1995), reminiscent of the situation described for the species-specific propiverine-induced rDAAO accumulation.…”

Species-specific Inflammatory Responses as a Primary Component for the Development of Glomerular Lesions in Mice and Monkeys Following Chronic Administration of a Second-generation Antisense Oligonucleotide

“…The combination of glomerular dysfunction and interstitial deposition of amyloidosis likely resulted in the secondary papillary changes that occurred with drisapersen and resulted in premature deaths. Interstitial amyloidosis is a well-recognized cause of papillary necrosis in mice (Frazier et al 2012), possibly related to ischemia of the distal medulla via progressive loss of the vascular supply through occlusion of the medullary vasculature (Frazier and Seely 2013). Lysosomes are intimately linked with amyloid fibril formation and provide an environment conducive to the transition from helical to b-pleated sheet structure.…”

Extended One-Generation Reproductive Toxicity Test in Rats Exposed to 3-Nitro-1,2,4 Triazol-5-One (NTO), October 2013-March 2014

“…The observation, however, resembles apoptosis ( Figure 7). It has been reported (Frazier et al, 2012) that the S3 segment of the proximal tubule, which is in the pars recta (outer stripe), is acutely sensitive to hypoxia and therefore begins autolysis immediately upon euthanasia. This suggests a similar mechanism accounts for this change in the renal inner stripe (not observed in the outer stripe in this study), which was present to varying extent in both treated and control animals.…”