Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor-α-converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose-stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose-induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE-heparin-binding epidermal growth factor-EGFR-MAPK-signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy.

译文

:长期暴露于高葡萄糖会导致糖尿病肾病,其特征是肾小球系膜基质蛋白(例如胶原蛋白)蓄积增加。已经记录了改变的细胞信号传导和基因表达并伴有氧化应激。检查了对氧化应激敏感的酪氨酸激酶c-Src(Src)的贡献。在存在和不存在Src抑制剂(PP2,SU6656),Src小干扰RNA(siRNA)和肿瘤坏死因子-α转化酶(TACE)的情况下,将培养的大鼠肾小球系膜细胞暴露于高葡萄糖(25 mmol / L)抑制剂,TAPI-2。通过对链脲佐菌素(STZ)诱导的糖尿病DBA2 / J小鼠施用PP2在体内研究了Src。高葡萄糖刺激的Src,TACE,表皮生长因子受体(EGFR),有丝分裂原激活的蛋白激酶(MAPK),细胞外信号调节激酶(ERK1 / 2,p38)和胶原IV在肾小球膜细胞中的蓄积。 PP2和SU6656阻止了Src Tyr-416,EGFR和MAPK的高葡萄糖刺激磷酸化。这些抑制剂和siRNA以及SAPI敲除的Src敲除也废除了高葡萄糖诱导的这些靶标的磷酸化和胶原IV的积累。在STZ糖尿病小鼠中,白蛋白尿,Src pTyr-416升高,TACE活化,ERK和EGFR磷酸化,肾小球胶原蛋白积聚和足细胞丢失均被PP2抑制。这些数据表明Src在高葡萄糖-Src-TACE-肝素结合表皮生长因子-EGFR-MAPK信号通路中积累胶原蛋白的作用。因此,Src可以为糖尿病性肾病提供新的治疗靶标。

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