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Inflammation Research

, Volume 67, Issue 11–12, pp 1013–1019 | Cite as

PKA regulates HMGB1 through activation of IGFBP-3 and SIRT1 in human retinal endothelial cells cultured in high glucose

  • Li Liu
  • Paragi Patel
  • Jena J. SteinleEmail author
Original Research Paper
  • 177 Downloads

Abstract

Objective and Design

Inflammation is a key component of a number of diseases, including diabetic retinopathy. We investigated the cellular pathway by which protein kinase A (PKA) inhibited high mobility group box 1 (HMGB1).

Methods

Primary human retinal endothelial cells (REC) were grown in normal glucose (5 mM) or high glucose (25 mM). Cells in high glucose were treated with exchange protein for cAMP 1 (Epac1) and IGFBP-3 siRNA. Additional cells in high glucose were treated with forskolin, a PKA agonist, and Epac1 siRNA. Some cells were treated with a plasmid for insulin-like growth factor binding protein 3 (IGFBP-3) that does not bind IGF-1. Finally, some REC received Ex527, a sirtuin 1 (SIRT1) antagonist, prior to forskolin treatment. Protein analyses were done for HMGB1, Epac1, IGFBP-3, SIRT1, and PKA.

Results

PKA inhibited cytoplasmic HMGB1, independent of Epac1 actions. PKA activated IGFBP-3 and SIRT1 to inhibit cytoplasmic HMGB1. High glucose inhibited SIRT1 levels and increased cytoplasmic HMGB1 in REC.

Conclusions

PKA requires active IGFBP-3 and SIRT1 to inhibit HMGB1 inflammatory actions in the retina vasculature. Activation of these pathways may offer new targets for therapy development.

Keywords

PKA HMGB1 SIRT1 Inflammation Retinal endothelial cells 

Notes

Acknowledgements

R01EY028442 (JJS), P30EY04068 (Hazlett), and an Unrestricted Grant to the Department of Ophthalmology from Research to Prevent Blindness (Kresge Eye Institute). The funders did not influence these design or execution of these studies.

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Ophthalmology, Visual and Anatomical SciencesWayne State University SOMDetroitUSA

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