Intermittent But Not Constant High Glucose Induces ER Stress and Inflammation in Human Retinal Pericytes

  • Yimin Zhong
  • Joshua J. Wang
  • Sarah X. ZhangEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


Diabetic retinopathy is a chronic inflammatory disease characterized by vascular damage and neuronal degeneration. Previously, we reported that activated retinal pericytes secret high levels of proinflammatory cytokines, such as macrophage chemoattractant protein 1 (MCP-1), and may play a pivotal role in macrophage recruitment and inflammatory retinal damage. However, the mechanism underlying diabetes-induced pericyte inflammation remains poorly understood. In the present study, we evaluated the effects of constant and intermittent high glucose on inflammatory cytokine production in human retinal pericytes (HRP) and explored the role of endoplasmic reticulum (ER) stress in pericyte inflammation. We found that intermittent high glucose, but not constant high glucose, increases MCP-1 secretion and expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key mediators of ER stress-associated inflammation and cell death. Inhibition of ER stress by chemical chaperones successfully prevented glucose fluctuation-induced ATF4/CHOP activation and inflammatory cytokine production. Our results suggest that activation of ER stress by glucose fluctuation may play a causal role in pericyte injury and inflammation in diabetic retinopathy.


Endoplasmic reticulum stress Inflammation Retinal pericyte MCP-1 CHOP Diabetic retinopathy 



This work was supported by National Institutes of Health grant EY019949; Research Award 5-2009-475 from Juvenile Diabetes Research Foundation; Research Grants HR07-167 and HR10-060 from Oklahoma Center for the Advancement of Science and Technology; Research Grant M2010088 from American Health Assistance Foundation; and Dr. William Talley Research Award from Harold Hamm Oklahoma Diabetes Center.


  1. Beltramo E, Berrone E, Tarallo S et al (2009) Different apoptotic responses of human and bovine pericytes to fluctuating glucose levels and protective role of thiamine. Diabetes Metab Res Rev 25:566–576PubMedCrossRefGoogle Scholar
  2. Endo M, Mori M, Akira S et al (2006) C/EBP Homologous Protein (CHOP) Is Crucial for the Induction of Caspase-11 and the Pathogenesis of Lipopolysaccharide-Induced Inflammatio. J Immunol 176:6245–6253PubMedGoogle Scholar
  3. Gorbatyuk MS, Knox T, LaVail MM et al. (2010) Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc Natl Acad Sci U S A 107:5961–5966PubMedCrossRefGoogle Scholar
  4. Ikesugi K, Mulhern ML, Madson CJ et al (2006) Induction of endoplasmic reticulum stress in retinal pericytes by glucose deprivation. Curr Eye Res 31:947–953PubMedCrossRefGoogle Scholar
  5. Inokuchi Y, Nakajima Y, Shimazawa M et al (2008) Effects of an Inducer of BiP, a Molecular Chaperon, on Endoplasmic Reticulum (ER) Stress-Induced, Limits Retinal Cell Death. Invest Ophthalmol Vis Sci 50:334–344Google Scholar
  6. Li J, Wang JJ, Yu Q et al (2009a) Endoplasmic Reticulum Stress is implicated in Retinal Inflammation and Diabetic Retinopathy. FEBS Lett 183:1521–1527Google Scholar
  7. Li J, Wang JJ, Chen D et al (2009b) Systemic administration of HMG-CoA reductase inhibitor protects the blood-retinal barrier and ameliorates retinal inflammation in type 2 diabetes. Exp Eye Res 89:71–78Google Scholar
  8. Piconi L, Quagliaro L, Da Ros R et al (2004) Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase. J Thromb Haemost 2:1453–1459PubMedCrossRefGoogle Scholar
  9. Quagliaro L, Piconi L, Assaloni R et al (2003) Intermittent High Glucose Enhances Apoptosis Related to Oxidative Stress in Human Umbilical Vein Endothelial Cells. Diabetes 52:2795–2804PubMedCrossRefGoogle Scholar
  10. Song B, Scheuner D, Ron D et al (2008) Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest 118:3378–3389PubMedCrossRefGoogle Scholar
  11. Zhang SX, Wang JJ, Dashti A et al (2008) Pigment epithelium-derived factor (PEDF) mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized-LDL. J Mol Endocrinol 41:135–143PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yimin Zhong
    • 1
    • 2
  • Joshua J. Wang
    • 1
  • Sarah X. Zhang
    • 1
    Email author
  1. 1.Department of Medicine, Endocrinology and Diabetes, Harold Hamm Oklahoma Diabetes CenterUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhouChina

Personalised recommendations