EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy
EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy
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DOI：
10.1681/asn.2014020192
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发表时间：
2015-05-01
影响因子：
13.6
通讯作者：
Harris, Raymond C.
中科院分区：
文献类型：
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作者：
Chen, Jianchun;Chen, Jian-Kang;Harris, Raymond C.
损伤或功能障碍的线粒体产生的活性氧物种(ROS)，特别是超氧化物歧化，被认为是糖尿病并发症发生的始动事件。肾小球是糖尿病肾小球损伤的主要部位，足细胞损伤是糖尿病肾小球病变的典型特征。在链脲佐菌素诱导的1型糖尿病中，足细胞特异性EGF受体(EGFR)基因敲除小鼠(PodKO)及其野生型(WT)小鼠的高血糖和多尿水平相似，但与WT糖尿病小鼠相比，EGFR(PodKO)小鼠的蛋白尿和足细胞丢失显著减少。此外，EGFR(PodKO)糖尿病小鼠肾小球纤维连接蛋白沉积、Smad2/3磷酸化和转化生长因子-β1表达减少。肾小球裂解物免疫印迹结果显示，EGFR(PodKO)糖尿病小鼠肾小球裂解caspase3表达上调和bcl2表达下调在EGFR(PodKO)糖尿病小鼠中得到减弱。给予超氧化物歧化酶类似物Mito-temol或NADPH氧化酶抑制剂apocynin可减轻WT糖尿病小鼠肾小球p-c-Src、p-EGFR、p-ERK1/2、p-Smad2/3和转化生长因子-β1的表达上调，并阻止裂解caspase 3和bcl2表达的改变。培养的小鼠足细胞经高糖处理后，ROS的产生、c-Src、EGFR和Smad2/3的磷酸化以及转化生长因子-β1、裂解半胱氨酸酶3和bcl2的表达也发生了类似的变化。使用mito-temol或apocynin或通过抑制EGFR的表达或活性可抑制这些变化。因此，我们利用足细胞特异性EGFR缺失的小鼠进行的研究结果表明，EGFR激活在糖尿病肾病中介导足细胞损伤和丢失的激活途径中起主要作用。
The generation of reactive oxygen species (ROS), particularly superoxide, by damaged or dysfunctional mitochondria has been postulated to be an initiating event in the development of diabetes complications. The glomerulus is a primary site of diabetic injury, and podocyte injury is a classic hallmark of diabetic glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific EGF receptor (EGFR) knockout mice (EGFR(PodKO)) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFR(PodKO) mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFR(PodKO) diabetic mice had less TGF-beta 1 expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition. Immunoblotting of isolated glomerular lysates revealed that the upregulation of cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated in EGFR(PodKO) diabetic mice. Administration of the SOD mimetic mito-tempol or the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src, p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-beta 1 expression and prevented the alteration of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice. High-glucose treatment of cultured mouse podocytes induced similar alterations in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and expression of TGF-beta 1, cleaved caspase 3, and Bcl2. These alterations were inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR expression or activity. Thus, results of our studies utilizing mice with podocyte-specific EGFR deletion demonstrate that EGFR activation has a major role in activating pathways that mediate podocyte injury and loss in diabetic nephropathy.