Joshua J. Wang
State University of New York
USA
Title: Endoplasmic reticulum homeostasis and inflammation in retinal muller cells
Biography
Biography: Joshua J. Wang
Abstract
Increasing evidence suggests that endoplasmic reticulum (ER) stress and inflammation contributes to the pathogenesis of diabetic retinopathy (DR), a leading cause of blindness in working-age population. Müller glia cells, which constitute the major glial component of the retina, are considered major source of inflammatory factors in DR. In the present study, we investigated the role of ER stress in Müller cell inflammation using conditional knockout (Xbp1Müller-/-) mice that lack X-box binding protein 1 (XBP1) in Müller cells. Diabetes was induced by streptozotocin in male adult Xbp1Müller-/- mice and their littermate controls (Xbp1Müller+/+). Expression of retinal ER stress markers and inflammatory cytokines was examined by real-time qPCR, Western blotting and immunostaining. Retinal vascular permeability was measured by FITC-conjugated dextran method after 2 months of diabetes. Xbp1Müller-/- mice exhibit normal retinal development and retinal function determined by ERG. In diabetic mice, mRNA and protein levels of major inflammatory cytokines (VEGF and TNF-α) were significantly increased in retinas of Xbp1Müller-/- mice compared to control mice. In addition, XBP1 deficiency resulted in greater ER stress in diabetic retinas, as evidenced by enhanced expression of GRP78, p-eIF2α, ATF4, CHOP, ATF6 and p-JNK. Consistently, retinal vascular permeability was significantly increased in diabetic Xbp1Müller-/- mice compared to the control. Increased ER stress and inflammatory gene expression was confirmed in retinal Müller cells isolated from Xbp1Müller-/- mice. Taken together, our results indicate that increased ER stress in Müller cell is an important contributing factor in inflammatory cytokine production and inflammation-related vascular damage in DR.