Pigment epithelium-derived factor (PEDF) inhibits proximal tubular cell injury in early diabetic nephropathy by suppressing advanced glycation end products (AGEs)-receptor (RAGE) axis
Pigment epithelium-derived factor (PEDF) inhibits proximal tubular cell injury in early diabetic nephropathy by suppressing advanced glycation end products (AGEs)-receptor (RAGE) axis
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DOI：
10.1016/j.phrs.2010.11.008
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发表时间：
2011-03-01
影响因子：
9.3
通讯作者：
Yamagishi, Sho-ichi
中科院分区：
文献类型：
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作者：
Maeda, Sayaka;Matsui, Takanori;Yamagishi, Sho-ichi
色素上皮衍生因子（PEDF）是一种具有抗血管生成和抗炎作用的多功能糖蛋白，可阻断实验性糖尿病视网膜病变的发生和发展。然而，PEDF在早期实验性糖尿病肾病中的作用还不完全清楚。晚期糖基化终末产物（AGES）及其受体（RECEPTOR）轴刺激氧化应激产生，随后引起肾小管细胞中的炎症和纤维化反应，从而在糖尿病肾病中发挥作用。因此，本研究探讨PEDF是否可以预防早期糖尿病肾病中AGE引起的肾小管细胞损伤。在PEDF存在或不存在的情况下，人近端肾小管细胞与或不与AGE-牛血清白蛋白一起孵育。链脲佐菌素诱导的糖尿病大鼠静脉注射或不注射PEDF治疗4周。通过实时定量逆转录聚合酶链反应分析基因表达。用二氢乙锭染色法测定活性氧（ROS）。PEDF或抗人肾小管上皮细胞抗体抑制AGE诱导的肾小管上皮细胞基因表达，随后降低近端肾小管上皮细胞ROS生成、单核细胞趋化蛋白-1（MCP-1）和转化生长因子-β（TGF-β）、纤连蛋白和IV型胶原mRNA水平。PEDF可抑制糖尿病大鼠肾脏中TGF-β和MCP-1 mRNA的表达、ROS的产生以及MCP-1和TGF-β mRNA的表达。我们目前的数据表明，PEDF可以发挥保护作用，对肾小管损伤的糖尿病肾病减轻AGEs的有害影响，通过下调表达。PEDF的管理可能会提供一个有前途的策略，阻止糖尿病肾病的发展。(C)2010爱思唯尔有限公司版权所有。
Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein with anti-angiogenic and anti-inflammatory properties, and it could block the development and progression of experimental diabetic retinopathy. However, a role for PEDF in early experimental diabetic nephropathy is not fully understood. Advanced glycation end products (AGES) and their receptor (RAGE) axis stimulates oxidative stress generation and subsequently evokes inflammatory and fibrogenic reactions in renal tubular cells, thereby playing a role in diabetic nephropathy. Therefore, this study investigated whether PEDF could prevent AGE-elicited tubular cell injury in early diabetic nephropathy. Human proximal tubular cells were incubated with or without AGE-bovine serum albumin in the presence or absence of PEDF. Streptozotocin-induced diabetic rats were treated with or without intravenous injection of PEDF for 4 weeks. Gene expression was analyzed by quantitative real-time reverse transcription-polymerase chain reactions. Reactive oxygen species (ROS) was measured with dihydroethidium staining. PEDF or antibodies raised against RAGE inhibited the AGE-induced RAGE gene expression and subsequently reduced ROS generation, monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta (TGF-beta), fibronectin and type IV collagen mRNA levels in proximal tubular cells. RAGE gene expression, ROS generation and MCP-1 and TGF-beta mRNA levels were significantly increased in diabetic kidney, which were suppressed by administration of PEDF. Our present data suggest that PEDF could play a protective role against tubular injury in diabetic nephropathy by attenuating the deleterious effects of AGEs via down-regulation of RAGE expression. Administration of PEDF may offer a promising strategy for halting the development of diabetic nephropathy. (C) 2010 Elsevier Ltd. All rights reserved.