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The present study was designed to examine the effect of aldose reductase (AR) overexpression on the development of diabetic neuropathy by using mice transgenic for human AR. At 8 weeks of age, transgenic mice (Tg) and non-transgenic littermates (Lm) were made diabetic with streptozotocin. After 8 weeks of untreated diabetes, plasma glucose levels and the reduction in body weight were similar between the groups of diabetic animals. Despite the comparable levels of hyperglycaemia, levels of sorbitol and fructose were significantly greater in the peripheral nerve of diabetic Tg than in diabetic Lm (both P < 0.01). Ouabain sensitive Na(+),K(+)-ATPase activity was similarly decreased in both diabetic Tg and Lm. Protein kinase C activity in the sciatic nerve membrane fraction was unaffected by diabetes in Lm, but was reduced by nearly 40% in the diabetic Tg. Although both groups of diabetic animals exhibited a significant decrease in tibial nerve motor nerve conduction velocity (MNCV), this decrease was significantly more severe (P < 0.01) in diabetic Tg than in diabetic Lm. Consistent with these findings, nerve fibre atrophy was significantly more severe in diabetic Tg than in diabetic Lm (P < 0.01). These findings implicate increased polyol pathway activity in the pathogenesis of diabetic neuropathy. In support of this hypothesis, treating diabetic Tg with an aldose reductase inhibitor (WAY121-509, 4 mg/kg/day) for 8 weeks significantly prevented the accumulation of sorbitol, the decrease in MNCV and the increased myelinated fibre atrophy in diabetic Tg.

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The neu oncogene (also referred to as c-erbB-2 and HER2) encodes a 185-kDa transmembrane glycoprotein with tyrosine kinase activity termed p185. The p185 glycoprotein is structurally related to the epidermal growth factor receptor. It is thought that p185 is the receptor for an as yet unidentified growth factor. In the present study, RNA blot analyses and immunohistochemical studies were performed on rat tissues obtained from a variety of prenatal and postnatal stages to examine the expression of the neu oncogene and its product, p185, during normal development. Expression of the neu gene was detected in mid-gestation embryos in a variety of tissues including nervous system, connective tissue, and secretory epithelium, but not in lymphoid tissue. In adult animals, secretory epithelial tissues and basal cells of the skin expressed neu. These studies demonstrate that the neu gene is expressed in a tissue-and developmental stage-specific manner. We suggest that the p185 molecule plays an important role in the growth and development of a variety of tissues, and, in particular, in epithelial tissue.The neu oncogene was first identified as a transforming gene of ethylnitrosourea-induced rat neuroblastomas (1). Nucleotide sequence analysis of neu complementary DNA and biochemical study of the neu gene product demonstrated that the gene encodes a 185-kDa protein closely homologous to, but distinct from, the epidermal growth factor receptor (1, 2, 3). The protein product, termed p185, consists of an extracellular putative binding domain, a transmembrane anchoring domain, and an intracytoplasmic tyrosine kinase domain. The c-erbB-2/HER2 gene, isolated as a v-erbB-related gene, appears to represent the human counterpart of the rat neu gene (4, 5).The expression of p185 is necessary for maintenance of the malignant phenotype of cell lines transformed by neu (6). In addition, recent studies demonstrate amplification of the human form of neu in several human adenocarcinomas, including those of breast (7,8), salivary gland (9), stomach (9, 10, 11), and kidney (9).To elucidate the potential biological function of this recently described receptor-like molecule in normal cells and neoplasia, we sought to determine whether the neu gene is expressed in normal developing rat tissues. Using RNA blot analysis and immunohistochemistry, we demonstrate that the expression of the neu gene and its product, p185, are expressed during normal development in the rat in a tissue-and stage-specific manner. MATERIALS AND METHODSRNA Blot Analysis. Total tissue RNA was prepared from whole embryos at embryonal day 14 (E14), E16, E18, and from individual organs of E18 embryos and older animals.Fetal ages were estimated from the probable time of impregnation of the mothers and were confirmed by morphological criteria (12) and by measurement of the crown-rump length (13). RNA was prepared by the guanidine isothiocyanate cesium chloride method (14). RNA (20 Ag per lane) was electrophoresed in a 1% agarose/2.2 M formaldehyde gel (15) and transfer...