The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism
Year: 2017
Type: article
Abstract: Retinal microaneurysms, an early disease manifestation of diabetic retinopathy, are associated with retinal endothelial cell (REC) death and macular edema. We previously demonstrated that a quinic acid (QA) analog, KZ-41, promoted REC survival by blunting stress-induced p38 MAPK activation. Herein, we sought to expand our understanding of the pro-survival signal transduction pathways actuated by KZ-41. Using human RECs exposed to high glucose (25 mM, 72 hours), we demonstrated that KZ-41 blocks caspase-3 activation by triggering phosphorylation of the PI3K regulatory subunit (p85; Tyr458) and its downstream target Akt (Ser473). Akt signal transduction was accompanied by autophosphorylation of the receptor tyrosine kinase, insulin growth factor-1 receptor (IGF-1R). IGF-1R knockdown using either the tyrosine kinase inhibitor AG1024 or silencing RNA abolished KZ-41's pro-survival effect. Under high glucose stress, caspase-3 activation correlated with elevated ERK1/2 phosphorylation and decreased insulin receptor substrate-1 (IRS-1) levels. KZ-41 decreased ERK1/2 phosphorylation and reversed the glucose-dependent reduction in IRS-1. To gain insight into the mechanistic basis for IGF-1R activation by KZ-41, we used molecular modeling and docking simulations to explore a possible protein:ligand interaction between the IGF-1R kinase domain and KZ-41. Computational investigations suggest two possible KZ-41 binding sites within the kinase domain: a region with high homology to the insulin receptor contains one potential allosteric binding site, and another potential site on the other side of the kinase domain, near the hinge domain. These data, together with previous proof-of-concept efficacy studies demonstrating KZ-41 mitigates pathologic retinal neovascularization in the murine oxygen-induced retinopathy model, suggests that QA derivatives may offer therapeutic benefit in ischemic retinopathies.
Source: PLoS ONE
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: Research to Prevent Blindness, St. Giles Foundation, U.S. Public Health Service, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Oak Ridge National Laboratory
Awards: G3819548764, Compound 49b Prevents Retinal Endothelial Cell Death Through IGFBP-3 Levels, Mechanotransduction in Acute Lung Injury, Treatment with KZ-41 and OTP promotes wound healing in a radiation combined injur, CORE GRANT FOR VISION RESEARCH, G8261518204, Michigan Diabetes Research Center (MDRC)
OpenAlex ID: W2743219325