Role of endoplasmic reticulum stress in the loss of retinal ganglion cells in diabetic retinopathy

Abstract  
  Endoplasmic reticulum stress is closely involved in the early stage of diabetic retinopathy. In the present study, a streptozotocin-induced diabetic animal model was given an intraperitoneal injection of tauroursodeoxycholic acid. Results from immunofluorescent co-localization experiments showed that both caspase-12 protein and c-Jun N-terminal kinase 1 phosphorylation levels significantly increased, which was associated with retinal ganglion cell death in diabetic retinas. The C/ERB homologous protein pathway directly contributed to glial reactivity, and was subsequently responsible for neuronal loss and vascular abnormalities in diabetic retinopathy. Our experimental findings indicate that endoplasmic reticulum stress plays an important role in diabetes-induced retinal neuronal loss and vascular abnormalities, and that inhibiting the activation of the endoplasmic reticulum stress pathway provides effective protection against diabetic retinopathy.

Diabetic   retinopathy   is   one   of   the   most common complications associated with diabetes mellitus and the leading cause of blindness in adults. 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.  The death of neurons is irreversible and directly affects visual function. The most severely affected neurons in diabetic retinopathy are retinal ganglion cells.  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.  Persistent and intense ER stress can trigger apoptosis by induction of   the   caspase-12-dependent   pathway, c-Jun NH2-terminal kinase pathway and C/ERB homologous protein pathway.  ER stress is reported to be involved in the pathogenesis of various neuronal diseases in the brain and retina.

Growing evidence also indicates that ER stress is closely involved in the early stage of diabetic retinopathy.

Over-stimulation of neurons by glutamate, which is elevated in the vitreous of diabetic patients, may activate ER stress in retinal ganglion   cells   and   subsequently   lead   to death of retinal ganglion cells in the mouse.

An in vitro study showed that a low or sudden reduction of glucose levels activated ER stress and resulted in apoptosis of cultured retinal pericytes.  Afterwards,  ER stress regulated the over-expression of vascular endothelium growth factor,  which was responsible for vascular leakage and neovascularization. 
Tauroursodeoxycholic acid is a hydrophilic bile acid 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 replacement therapy for treatment of certain cholestatic syndromes.
Tauroursodeoxycholic acid also functions as a chemical chaperone and alleviates ER stress both in vivo and in vitro.  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 demonstrated 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.

Liping Yang, Lemeng Wu, Dongmei Wang, Ying Li, Hongliang Dou, Mark O.M.Tso, Zhizhong Ma