However, the difference between diabetic rats with or without tauroursodeoxycholic acid treatment was not significant in terms of blood glucose levels and body weight (Table 1). == Table 1. caspase-12 protein, C/ERB homologous protein, retinal microcirculation, glial fibrillary acidic protein, grant-supported paper, neuroregeneration Research Highlights Endoplasmic reticulum stress plays an important role in the hyperglycemia-induced death of ganglion cells and impairment of retinal microvessels. Tauroursodeoxycholic acid treatment effectively inhibited the activation of the endoplasmic reti-culum stress pathway, and provided effective protection against diabetic retinopathy. Both caspase-12 protein and phosphorylated c-Jun N-terminal kinase 1 levels significantly in-creased, and they were associated with retinal ganglion cells in diabetic retinas. The C/ERB homologous protein was shown to co-localize with glial fibrillary acidic tein-positive glial cells in the retina of diabetic rats, and subsequently provided evidence for the tivation of glial cells in diabetic retinopathy. == INTRODUCTION == Diabetic retinopathy is one of the most common complications associated with diabetes mellitus and the leading cause of blindness in adults[1]. Mechanisms underlying diabetic retinopathy onset and progression are not fully elucidated. Both neuronal and vascular abnormalities are associated with the pathogenesis of early diabetic retinopathy[2]. The death of neurons is usually irreversible and directly affects visual function. The most severely affected neurons in diabetic retinopathy are retinal ganglion cells[3]. Therefore, understanding the etiology of neuronal loss and vascular abnormalities will lead to better treatments for diabetic retinopathy. The endoplasmic reticulum (ER) has received much attention for its role in signal transduction relevant to cell survival and death. A number of pathophysiological insults lead to ER stress[4]. SSR240612 Persistent and intense ER stress can trigger apoptosis by induction of the caspase-12-dependent pathway[5], c-Jun NH2-terminal kinase pathway[6] and C/ERB homologous protein pathway[7]. ER stress is usually reported to be involved in the pathogenesis of various neuronal diseases in the brain and retina[6,8,9,10]. Growing evidence also indicates that ER stress is usually closely involved in the early stage of diabetic retinopathy[11]. Over-stimulation of neurons by glutamate, which is usually elevated in the vitreous of diabetic patients[12], may activate ER stress in retinal ganglion cells and subsequently lead to death of retinal ganglion cells in the mouse[13]. Anin vitrostudy showed that a low or sudden reduction of glucose levels activated ER stress and resulted in apoptosis of cultured retinal pericytes[14]. Afterwards, ER stress regulated SSR240612 the over-expression of vascular endothelium growth factor, which was responsible for vascular leakage and neovascularization[15]. Tauroursodeoxycholic acid is usually a hydrophilic bile acid SSR240612 that is normally produced endogenously in humans at very low levels. Tauroursodeoxycholic acid is formed in the conjugation pathway of ursodeoxycholic acid, which is commonly used as a bile acid alternative therapy for treatment of certain cholestatic syndromes[16]. Tauroursodeoxycholic acid also functions as a chemical chaperone and alleviates ER stress bothin vivoandin vitro[17,18]. Although major progress has been achieved, there is still no clear evidence directly associating ER stress with the pathogenesis of diabetic retinopathy. We propose that ER stress plays an important role in diabetic retinopathy, and this study exhibited that (1) the expression of ER stress marker proteins was significantly elevated in streptozotocin (STZ)-induced diabetic retinas; and (2) tauroursodeoxycholic acid treatment effectively inhibited diabetes-induced ER stress marker protein expression, and appeared to protect diabetic retinas from neuronal cell death and vascular abnormality. == RESULTS == == Quantitative analysis of experimental animals == Fifty-four Sprague-Dawley rats aged 8 weeks, weighing 180 g, were randomly divided into three groups: control group (normal feeding), diabetic group (diabetes mellitus models were established Rabbit polyclonal to IPO13 with intraperitoneal injection of STZ), and tauroursodeoxycholic acid treatment group (diabetes mellitus was established and tauroursodeoxycholic acid 100 mg/kg was administered per day). Each group contained 18 rats. Rats were examined at 2, 4, 6 and 8 weeks after injection for measurements of body weight and blood glucose levels. All experimental rats were involved in the final analysis without any loss. == Changes of body weight and blood glucose levels in diabetic rats == From 2 to 8 weeks after onset of diabetes, the age-matched control rats had a 34% gain in body weight, whereas diabetic rats had a 12% gain in body weight, and tauroursodeoxycholic acid-treated diabetic rats had a 14% gain in body weight. Diabetic rats treated with or.