Protection of tauroursodeoxycholic acid on high glucose-induced human retinal microvascular endothelial cells dysfunction and streptozotocin-induced diabetic retinopathy rats
Graphical abstract
Introduction
Diabetes mellitus (DM) is a worldwide concern which has dramatically increased in recent years. Diabetic retinopathy (DR) is one of serious microvascular complication that affects the retina with symptoms appearing late after the onset of diabetes (Vlatka et al., 2015, Tapley et al., 2015). The change of blood composition in diabetic patients could cause abnormal function of vascular endothelium cells and then resulted in damaging blood retinal barrier. The studies have shown that several vascular, inflammatory and neuronal mechanisms are involved in the complex pathogenesis of DR (Semeraro et al., 2015). Therefore, the research about inflammatory and vascular related factors (ICAM-1, NOS, NF-κB p65 and VEGF) is highlighted.
Fel Ursi Pulvis getting from black bear (Selennarctos thibetanus Cuvier) or brown bear (Ursus arctos L.) in Ursidae family, a traditional Chinese medicine, has remarkable functions on “Clearing heat and detoxification, removing liver fire for improving eyesight” (Wang and Carey, 2014). Tauroursodeoxycholic acid (TUDCA), a major bile acid in bear gall, is formed by the conjugation of ursodeoxycholic acid (UDCA) with taurine and can be obtained by synthetic methods. (Gaspar et al., 2013, Xu et al., 2015). This endogenous hydrophilic bile acid, acts as a mitochondrial stabilizer and anti-apoptotic agent in several models of neurodegenerative diseases (Castro-Caldas et al., 2012, Yanguas-Casás et al., 2014). Multiple pharmacological activities of TUDCA have been shown to be neuroprotective in AD (Ramalho et al., 2013, Dionísio et al., 2015), prevention of acute kidney injury (Gupta et al., 2012), pancreatitis (Malo et al., 2010, Seyhun et al., 2011).
In recent years, there are some reports about the protection of TUDCA on retinopathy (Mantopoulos et al., 2011, Noailles et al., 2014). TUDCA could prevent vision loss in diseases and neurodegenerative diseases including retinitis pigmentosa (Mantopoulos et al., 2011, Noailles et al., 2014). Retinas of TUDCA-treated mice had thicker outer nuclear layers, more photoreceptor cells, and more fully-developed photoreceptor outer segments (Gaspar et al., 2013). However, whether TUDCA is effective on DR is unknown. Therefore, this study was conducted to evaluate the protection of TUDCA on high glucose-induced HRMECs dysfunction and STZ-induced DR rats and the possible mechanism was explored.
Section snippets
Chemicals and reagents
DMEM medium with high-glucose (4.5 g/L), DMEM medium with low-glucose (1.0 g/L) and trypsin were provided by KeyGEN Biotech Co., Ltd (Nanjing, China). NO (Lot: 20140715ELISA kits were purchased from Victoria Reagent Co., Ltd. (Shanghai, China). Fetal bovine serum (FBS) was purchased from Gibco/BRL (Grand Island, NY, USA). 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), dimethyl sulfoxide (DMSO), and streptozotocin (STZ) were provided by Sigma (St. Louis, MO, USA).
High glucose-induced HRMECs proliferation
MTT assay was used to determine cell proliferation. As shown in Fig. 2, the viability of cells induced by high glucose-DMEM medium (4.5 g/L) was obviously higher than that in low glucose-DMEM medium (1.0 g/L) at 24 h, 48 h and 72 h respectively. However, the enhancement of the cell viability stimulated by high glucose-DMEM medium (4.5 g/L) was decreased in a time-dependent manner. Delightedly, the treatment with TUDCA (1.0 μM, 5.0 μM, 25.0 μM and 125.0 μM) could decrease significantly the cell viability
Discussion and conclusions
DR, a type of specific fundus lesions, is one of the leading causes of visual impairment in the working-age population of the world (Semeraro et al., 2015). DR is mainly due to cells in the retina at a high glucose environment for a long time, leading to a series of fundus diseases, such as apoptosis, migration and proliferation of endothelial cells, cell permeability disorder, and retinal detachment. The multiple biological activities of TUDCA have been revealed, however, its potential
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Chun-fei Wang, Jia-rui Yuan and Dong Qin contributed equally to the work.