Spontaneously Occurring Formation of Intranuclear and Cytoplasmic Inclusions in Renal Proximal Epithelium Due to Accumulation of D-Amino Acid Oxidase in Wistar Hannover Rats.

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.

Regulation of adrenomedullin and its family peptide by RAMP system--lessons from genetically engineered mice.

Adrenomedullin (ADM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic molecule involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. Homozygotes of ADM knockout mice (ADM-/-) were lethal at mid-gestation with abnormalities of vascular development and this finding clarified the angiogenic potency of ADM. Calcitonin gene-related peptide (CGRP), which has a structure and function similar to that of ADM, has been identified as a family peptide of ADM. Unlike ADM-/-, CGRP-/- were apparently normal. Therefore, the study of knockout mice first clarified the distinctly different physiological roles between ADM and CGRP. In contrast, heterozygotes of ADM knockout mice (ADM+/-) were alive but showed blood pressure elevation, reduced neovascularization, and enhanced neointimal formation by arterial injury. Based on these observations, there was hope ADM would have a therapeutic use. However, ADM has a short half-life in the blood stream and its application in chronic disease has limitations. Therefore, we focused on the ADM receptor system. The calcitonin-receptor-like receptor (CLR), which is the ADM receptor, associates with one of the accessory proteins, called receptor activity-modifying proteins (RAMPs). By interacting with RAMP1, CLR exhibits a high affinity for CGRP, whereas by interacting with either RAMP2 or -3, CLR exhibits a high affinity for ADM. We generated RAMP knockout mice and found that vascular phenotypes similar to ADM-/- were reproduced only in RAMP2-/-. This shows that RAMP2 is the key determinant of the vascular functions of ADM. RAMP2 could be an attractive therapeutic target in cardiovascular diseases.

Spontaneous renal tumors suspected of being familial in sprague-dawley rats.

Spontaneous renal tubule tumors (RTTs), with a distinctive morphological phenotype, were present in three Sprague-Dawley rats, 1 male and 2 females, out a total of 120 animals of each sex from untreated and placebo control groups in a 2-year carcinogenicity study. One female had one carcinoma, adenoma and hyperplasia, and the other female had five adenomas and many hyperplastic lesions; the male case had one carcinoma. From these cases, a biological continuum of hyperplasia, adenoma and carcinoma could be recognized. The tumors were present in the renal cortex and appeared as solid lobulated growths with occasional central necrosis. The lobules were divided by a small amount of fibrovascular tissue. Occasionally the larger tumors contained a cystic area. Tumor cells appeared distinctive and exhibited variable amounts of eosinophilic/amphophilic and vacuolated cytoplasm. Nuclei were round to oval with a prominent nucleolus. Mitotic figures were uncommon, and no distant metastasis was noted. The tumors were seen as multiple and bilateral lesions in two animals and had no apparent relationship to chronic progressive nephropathy (CPN). Foci of tubule hyperplasia were also noted to contain the same type of cellular morphology. The morphological and biological features of these 3 cases resembled the amphophilic-vacuolar (AV) variant of RTT that has been posited to be of familial origin. This is a report of spontaneous familial renal tumors in Sprague-Dawley rats from Japan.

Destruction of salivary and lacrimal glands by Th1-polarized reaction in a model of secondary Sjögren's syndrome in lupus-prone female NZB × NZWF(1) mice.

T helper (Th)1/Th2 balance determines the direction of some kinds of autoimmune diseases. The involvement of acini areas by CD4(+) helper T(Th) cell subset in submandibular and lacrimal glands are largely unknown in secondary Sjögren's syndrome (sSjS) with systemic lupus erythematosus (SLE). Submandibular and lacrimal glands were examined immunopathologically in lupus-prone female NZB × NZW(B/W)F(1) mice, model for human sSjS with SLE. Dacryoadenitis and sialoadenitis with renal failure developed with age. Infiltration of lymphoid cells (lymphocytes and plasma cells) expanded from the periductal areas in striated ducts to the acini, and the isolated foci in the acini were observed in those organs. The destruction of duct and acini epithelium, including the myoepithelium, was induced by interferon (IFN)-γ(+) and IgG2a(+) lymphoid cells, but not by interleukin(IL)-4(+), IL-5(+), IL-13(+), and IgG1(+) lymphoid cells. Compared with IL-5 and IL-13, high values of IFN-γ were produced systemically at various ages. Also local expression of IFN-γ mRNA was higher than that of IL-4 mRNA. The result suggests that the acini destruction in submandibular and lacrimal glands may be induced by systemic and local Th1 cell dominant reactions in lupus-prone B/WF(1) mice with sSjS.

Superficial necrolytic dermatitis associated with extrapancreatic glucagonoma in a dog.

An 11-year-old Shih Tzu presented with crusting and erythema, mainly on the abdomen and the root of the tail. Based on histopathological findings, blood examinations and necropsy findings, the condition was diagnosed as superficial necrolytic dermatitis associated with a glucagon-secreting extrapancreatic neuroendocrine tumour. Gross necropsy revealed tumour invasion into the spleen, liver, adrenal glands and mesenteric lymph nodes. Immunohistochemical analysis of the neoplastic cells revealed that the tumour was a glucagonoma, consistent with earlier findings of persistent glucagonaemia and hypoaminoacidaemia.