Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Biomolecules. 2021 May 10;11(5):712. doi: 10.3390/biom11050712.
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 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.
为了研究血管内皮生长因子（VEGF）和脑源性神经营养因子（BDNF）在糖尿病视网膜病变（DR）中对 Muller 细胞（MC）活力和神经保护的作用机制，我们研究了 VEGF 在 MC 活力和 BDNF 产生中的作用，以及 BDNF 在糖尿病条件下对 MC 活力的影响。我们使用小鼠原代 MC 和大鼠 MC 系 rMC1 细胞来研究糖尿病条件下 MC 活力和 BDNF 产生。在小鼠中证实了 VEGF 刺激 BDNF 产生。使用 siRNA 敲低研究了 BDNF 介导的 MC 活力的机制。在糖尿病条件下，重组 VEGF（rVEGF）以剂量依赖性方式刺激 MC 活力和 BDNF 产生。rBDNF 也以剂量依赖性方式支持 MC 活力。用 siRNA 敲低靶向 BDNF 受体原肌球蛋白受体激酶 B（TRK-B）可显著下调丝氨酸/苏氨酸特异性蛋白激酶（AKT）和细胞外信号调节激酶（ERK）的激活（磷酸化）形式，这是经典的存活和增殖介质。最后，rBDNF 挽救了 siRNA 转染细胞在糖尿病条件下的 MC 活力丧失。我们的研究结果首次提供了直接证据，证明 VEGF 是糖尿病中 BDNF 产生的正向调节剂。这些信息对于开发 DR 和缺氧性视网膜疾病中的 BDNF 介导的神经保护以及改善这些血视网膜屏障疾病的抗 VEGF 治疗至关重要，在这些疾病中，VEGF 是血管异常的主要治疗靶标。
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