p75（NTR）的调节可预防糖尿病和 proNGF 诱导的小鼠和大鼠视网膜炎症和血视网膜屏障破坏。
Modulation of p75(NTR) prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats.
机构信息
Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, 1120 15th Street HM-1200, Augusta, GA 30912, USA.
出版信息
Diabetologia. 2013 Oct;56(10):2329-39. doi: 10.1007/s00125-013-2998-6. Epub 2013 Aug 7.
AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by early blood-retina barrier (BRB) breakdown and neurodegeneration. Diabetes causes imbalance of nerve growth factor (NGF), leading to accumulation of the NGF precursor (proNGF), as well as the NGF receptor, p75 neurotrophin receptor (p75(NTR)), suggesting a possible pathological role of the proNGF-p75(NTR) axis in the diabetic retina. To date, the role of this axis in diabetes-induced retinal inflammation and BRB breakdown has not been explored. We hypothesised that modulating p75(NTR) would prevent diabetes- and proNGF-induced retinal inflammation and BRB breakdown.
METHODS
Diabetes was induced by streptozotocin in wild-type and p75(NTR) knockout (p75KO) mice. After 5 weeks, the expression of inflammatory mediators, ganglion cell loss and BRB breakdown were determined. Cleavage-resistant proNGF was overexpressed in rodent retinas with and without p75(NTR) short hairpin RNA or with pharmacological inhibitors. In vitro, the effects of proNGF were investigated in retinal Müller glial cell line (rMC-1) and primary Müller cells.
RESULTS
Deletion of p75(NTR) blunted the diabetes-induced decrease in retinal NGF expression and increases in proNGF, nuclear factor κB (NFκB), p-NFκB and TNF-α. Deletion of p75(NTR) also abrogated diabetes-induced glial fibrillary acidic protein expression, ganglion cell loss and vascular permeability. Inhibited expression or cleavage of p75(NTR) blunted proNGF-induced retinal inflammation and vascular permeability. In vitro, proNGF induced p75(NTR)-dependent production of inflammatory mediators in primary wild-type Müller and rMC-1 cultures, but not in p75KO Müller cells.
CONCLUSIONS/INTERPRETATION: The proNGF-p75(NTR) axis contributes to retinal inflammation and vascular dysfunction in the rodent diabetic retina. These findings underscore the importance of p75(NTR) as a novel regulator of inflammation and potential therapeutic target in diabetic retinopathy.
目的/假设：糖尿病视网膜病变的特征是早期血视网膜屏障（BRB）破裂和神经退行性变。糖尿病导致神经生长因子（NGF）失衡，导致 NGF 前体（proNGF）以及 NGF 受体 p75 神经营养素受体（p75（NTR））的积累，表明 proNGF-p75（NTR）轴在糖尿病视网膜中可能具有病理作用。迄今为止，该轴在糖尿病引起的视网膜炎症和 BRB 破裂中的作用尚未得到探索。我们假设调节 p75（NTR）可以预防糖尿病和 proNGF 诱导的视网膜炎症和 BRB 破裂。
方法
链脲佐菌素（streptozotocin）诱导野生型和 p75（NTR）基因敲除（p75KO）小鼠发生糖尿病。 5 周后，测定炎症介质的表达，神经节细胞损失和 BRB 破裂。用杆状病毒短发夹 RNA 或药理学抑制剂在有和没有 p75（NTR）的啮齿动物视网膜中过表达无切割活性的 proNGF。在体外，研究了 proNGF 对视网膜 Müller 胶质细胞系（rMC-1）和原代 Müller 细胞的影响。
结果
p75（NTR）缺失减弱了糖尿病引起的视网膜 NGF 表达降低和 proNGF、核因子κB（NFκB）、p-NFκB 和 TNF-α的增加。p75（NTR）缺失还消除了糖尿病诱导的神经胶质纤维酸性蛋白表达、神经节细胞损失和血管通透性增加。抑制 p75（NTR）的表达或切割减弱了 proNGF 诱导的视网膜炎症和血管通透性。在体外，proNGF 在原代野生型 Müller 和 rMC-1 培养物中诱导 p75（NTR）依赖性炎症介质产生，但在 p75KO Müller 细胞中则没有。
结论/解释：proNGF-p75（NTR）轴有助于啮齿动物糖尿病视网膜中的视网膜炎症和血管功能障碍。这些发现强调了 p75（NTR）作为炎症的新型调节剂和糖尿病性视网膜病变潜在治疗靶点的重要性。
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