Akihito Shimoi

Human Natural Tumor Necrosis Factor α Induces Multiple Endocrine and Hematologic Disorders in Rats

Slc:Wistar male rats treated with human natural tumor necrosis factor α (hn TNF-α, 3 X 105 Japan reference units/kg intravenously) for 3 months showed histologic vacuolation of basophils in the anterior pituitary, hyperplasia of the thyroidal follicular epithelium, and hyperplasia of the testicular interstitial cells. The vacuolated basophils were immunohistochemically shown to be thyrotrophs. In addition, there were decreases in plasma levels of triiodothyronine (T3), thyroxin (T4), and testosterone, and an increase in thyroid-stimulating hormone (TSH). The number of lymphocytes in the marginal zones of lymphoid follicles in spleen and lymph nodes and B-lymphocytes in the peripheral blood decreased. Hyperplasia of hematopoietic cells in the bone marrow and decreases in both leukocytes and erythrocytes in the peripheral blood were prominent. Hyperplasia of bile ductular epithelial cells with periportal mononuclear cell infiltration in the liver and increased cellularity in alveolar walls in the lung were also characteristic. In in vitro studies, hn TNF-α inhibited both proliferation and peroxidase activity of thyroid follicular epithelial cells. These findings demonstrate that hn TNF-α may induce histologic vacuolation of thyrotrophs by causing a decrease in plasma levels of T3 and T4; hyperplasia of the thyroid follicular epithelium, which may be attributed to the increased plasma level of TSH; hyperplasia of testicular interstitial cells, by lowering the plasma level of testosterone; hyperplasia of bile ductular epithelial cells; hyperplasia of hematopoietic cells in bone marrow; and the increase in cellularity in pulmonary alveolar walls. In addition, hn TNF-α may suppress the differentiation of B-lymphocytes.

Unchanged Distribution Density of Anionic Sites on the Glomerular Wall in Rats with Streptozotocin-Induced Diabetic Nephropathy

As a cause of proteinuria in diabetic nephropathy, a decrease in anionic charge on the glomerular basement membrane (GBM) is considered to be related to protein leakage. However, the constancy of the anionic charge has been reported in several types of nephropathy. To elucidate the relation between glomerular protein leakage and anionic charge, we examined the distribution of anionic sites on the GBM and podocytes in diabetic rats induced by a single intravenous injection of 60 mg/kg of streptozotocin (STZ). Five months after the treatment with STZ, urinalysis for glucose and protein levels was conducted, and the kidneys were examined using electron microscopic cytochemistry for the assessment of anionic charge with two cationic probes. The distributions of anionic sites on the GBM demonstrated by two kinds of cationic markers in the diabetic rats were similar in density to those seen in the control animals. The distributions of anionic sites on the foot processes and cell membrane of podocytes were regular and also similar in density to that of the control group. From these results, we consider that the charge barrier of the GBM and podocytes is irrelevant to the protein leakage in diabetic rats.

Spontaneous Vacuolar Degeneration of the Thyroid Follicular Epithelium in Cynomolgus Monkeys

Vacuolar degeneration of the thyroid follicular epithelium was observed in two untreated female cynomolgus monkeys assigned to control groups. In light microscopy, large vacuoles containing a homogenous substance occupied the basal region of the epithelium, and the nuclei had shifted toward the apical region. The vacuoles showed negative reactions to PAS and thyroglobulin. Electron microscopic observation revealed dilatation of the rough endoplasmic reticulum corresponding to the vacuoles. The plasma TSH, T3 and T4 levels determined for the samples kept frozen were within the normal ranges, suggesting that the thyroid function was kept intact.

Unchanged Distribution Density of Anionic Sites on the Glomerular Wall in Rats with Active Heymann Nephritis

In various kinds of glomerulonephritis, alteration of anionic charge on the glomerular basement membrane (GBM) and podocytes has been controversial for more than decade. To elucidate the relation between glomerular protein leakage and anionic sites on the glomerular wall, we examined the distribution of anionic sites on the GBM and podocytes of rats with active Heymann nephritis (AHN). Urinalysis for protein levels was conducted, and the kidneys were examined using electron microscopic cytochemistry for the assessment of anionic charge with two cationic probes. The anionic sites on podocytes were decreased in number in the AHN rats; however, the distributions of anionic sites on the GBM were similar in density to those seen in the control animals. From these results, we consider that the decrease in anionic charge density on podocytes might be attributable to protein leakage and that the charge barrier of the GBM is irrelevant to the protein leakage in AHN rats.