Abstract
To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), we examined the role of VEGF in MC viability and BDNF production, and the effect of BDNF on MC viability under diabetic conditions. Mouse primary MCs and cells of a rat MC line, rMC1, were used in investigating MC viability and BDNF production under diabetic conditions. VEGF-stimulated BDNF production was confirmed in mice. The mechanism of BDNF-mediated MC viability was examined using siRNA knockdown. Under diabetic conditions, recombinant VEGF (rVEGF) stimulated MC viability and BDNF production in a dose-dependent manner. rBDNF also supported MC viability in a dose-dependent manner. Targeting BDNF receptor tropomyosin receptor kinase B (TRK-B) with siRNA knockdown substantially downregulated the activated (phosphorylated) form of serine/threonine-specific protein kinase (AKT) and extracellular signal-regulated kinase (ERK), classical survival and proliferation mediators. Finally, the loss of MC viability in TrkB siRNA transfected cells under diabetic conditions was rescued by rBDNF. Our results provide direct evidence that VEGF is a positive regulator for BDNF production in diabetes for the first time. This information is essential for developing BDNF-mediated neuroprotection in DR and hypoxic retinal diseases, and for improving anti-VEGF treatment for these blood–retina barrier disorders, in which VEGF is a major therapeutic target for vascular abnormalities.
Highlights
Introduction published maps and institutional affilMüller cells (MCs) are located in close proximity to almost all retinal functional components and cellular entities, including photoreceptors, secondary neurons, ganglion cells, vasculature, and vitreous
As excessive brainderived neurotrophic factor (BDNF) inside the MCs would most likely be secreted, we examined the levels of proBDNF in rMC1 cell extracts. recombinant VEGF (rVEGF) supplement resulted in an increase in proBDNF accumulation inside rMC1 cells cultured in NG media (Figure 2B)
MC viability are most likely very different from that of BDNF [31]. The presence of these compensatory mechanisms provides an opportunity to find treatment strategies for neuronal degeneration in diabetic retinopathy (DR) and other hypoxic retinal diseases in which vascular endothelial growth factor (VEGF) is a therapeutic target for blood–retina barrier (BRB) breakdown
Summary
Müller cells (MCs) are located in close proximity to almost all retinal functional components and cellular entities, including photoreceptors, secondary neurons, ganglion cells, vasculature, and vitreous This anatomical arrangement is ideal for MCs to serve as major retinal supporting cells that perform many essential functions, such as ion and water transport, energy metabolism, visual pigment recycling, synaptic activity, neural transmission, structural support and insulation, pathogen removal, anti-oxidative effect, blood–retina barrier (BRB) maintenance, cytokine and trophic factor production, neuroprotection, and neural progenitors and retinal regeneration (for review, see [1,2,3,4]). MCs respond to hyperglycemia/high retinal glucose and upregulate the production of inflammatory cytokines, BRB permeable factors, and neurotrophic factors, either by themselves or in conjunction with other cellular entities. iations.
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