REDD1-dependent GSK3β dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice.

Autor:	Sunilkumar S; Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA., VanCleave AM; Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA., McCurry CM; Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA., Toro AL; Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA., Stevens SA; Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA., Kimball SR; Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA., Dennis MD; Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania, USA; Department of Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania, USA. Electronic address: mdennis@psu.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Aug; Vol. 299 (8), pp. 104991. Date of Electronic Publication: 2023 Jun 29.
DOI:	10.1016/j.jbc.2023.104991
Abstrakt:	Increasing evidence supports a role for inflammation in the early development and progression of retinal complications caused by diabetes. We recently demonstrated that the stress response protein regulated in development and DNA damage response 1 (REDD1) promotes diabetes-induced retinal inflammation by sustaining canonical activation of nuclear transcription factor, NF-κB. The studies here were designed to identify signaling events whereby REDD1 promotes NF-κB activation in the retina of diabetic mice. We observed increased REDD1 expression in the retina of mice after 16 weeks of streptozotocin (STZ)-induced diabetes and found that REDD1 was essential for diabetes to suppress inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at S9. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented dephosphorylation of GSK3β and increased NF-κB activation in response to hyperglycemic conditions. Expression of a constitutively active GSK3β variant restored NF-κB activation in cells deficient for REDD1. In cells exposed to hyperglycemic conditions, GSK3β knockdown inhibited NF-κB activation and proinflammatory cytokine expression by preventing inhibitor of κB kinase complex autophosphorylation and inhibitor of κB degradation. In both the retina of STZ-diabetic mice and in Müller cells exposed to hyperglycemic conditions, GSK3 inhibition reduced NF-κB activity and prevented an increase in proinflammatory cytokine expression. In contrast with STZ-diabetic mice receiving a vehicle control, macrophage infiltration was not observed in the retina of STZ-diabetic mice treated with GSK3 inhibitor. Collectively, the findings support a model wherein diabetes enhances REDD1-dependent activation of GSK3β to promote canonical NF-κB signaling and the development of retinal inflammation. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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