Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition.
Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1α-VEGF pathway inhibition.
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作者：
Huang H;He J;Johnson D;Wei Y;Liu Y;Wang S;Lutty GA;Duh EJ;Semba RD
培育出一种新的糖尿病小鼠品系，Akita.PlGF 敲除 (−/−)，用于研究胎盘生长因子 (PlGF) 在糖尿病视网膜病变 (DR) 发病机制中的作用。 PlGF 缺失不会影响 Akita.PlGF−/− 小鼠的血糖，但会降低体重。这些小鼠预防了糖尿病引起的视网膜细胞死亡、毛细血管变性、周细胞损失和血视网膜屏障破坏。 PlGF 的蛋白表达因糖尿病而上调，尤其是在血管细胞中。由于 PlGF 缺乏，糖尿病引起的 ZO-1 和 VE-钙粘蛋白降解被逆转；它们的表达与声波刺猬和血管生成素-1的表达相关。秋田小鼠中 PlGF 缺失导致 Akt 磷酸化增加。糖尿病激活的缺氧诱导因子 (HIF)1α-血管内皮生长因子 (VEGF) 通路，包括 HIF1α、VEGF、VEGFR1-3 的表达以及磷酸化 (p)-VEGFR1、p-VEGFR2 和 p-内皮一氧化氮合酶的程度，在糖尿病患者的视网膜中受到抑制 PlGF−/− 小鼠。然而，细胞间粘附分子-1、血管细胞粘附分子-1、CD11b和CD18的表达不受PlGF缺失的抑制，视网膜白细胞停滞也不受抑制。这些结果表明，PlGF 对于 DR 的发展至关重要，其基因缺失可以保护视网膜免受糖尿病损伤。保护机制与 Akt 激活和 HIF1α-VEGF 通路抑制相关，但与糖尿病 PlGF−/− 小鼠视网膜中的视网膜白细胞停滞无关。
A new diabetic mouse strain, the Akita.PlGF knockout (−/−), was generated to study the role of placental growth factor (PlGF) in the pathogenesis of diabetic retinopathy (DR). PlGF deletion did not affect blood glucose but reduced the body weight of Akita.PlGF−/− mice. Diabetes-induced retinal cell death, capillary degeneration, pericyte loss, and blood-retinal barrier breakdown were prevented in these mice. Protein expression of PlGF was upregulated by diabetes, particularly in vascular cells. Diabetes-induced degradation of ZO-1 and VE-cadherin was reversed due to PlGF deficiency; their expression was correlated with that of sonic hedgehog and angiopoietin-1. PlGF deletion in Akita mice resulted in an increased Akt phosphorylation. Diabetes-activated hypoxia-inducible factor (HIF)1α–vascular endothelial growth factor (VEGF) pathway, including expression of HIF1α, VEGF, VEGFR1–3, and the extent of phospho (p)-VEGFR1, p-VEGFR2, and p–endothelial nitric oxide synthase, was inhibited in the retinas of diabetic PlGF−/− mice. However, expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, CD11b, and CD18 was not inhibited by PlGF deletion, nor was retinal leukostasis. These results suggest that PlGF is critical for the development of DR, and its genetic deletion protects the retina from diabetic damage. Protective mechanisms are associated with Akt activation and HIF1α-VEGF pathway inhibition, but independent of retinal leukostasis in the retinas of diabetic PlGF−/− mice.
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