Role of EGFR in high glucose and TGF-β1－induced cell growth and collagen production in NRK-49F cells

• Main Authors: Tai-Tu Lin, 林泰都
• Other Authors: Lea-Yea Chuang
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/96723604722697749899

碩士 === 高雄醫學大學 === 生物化學研究所碩士班 === 95 === Diabetic nephropathy (DN) is a common complication of diabetic mellitus. Hyperplycemia, advanced glycation end-product (AGE), angiotensin II (Ang II) and transforming growth factor beta1 (TGF-β1) play important roles in DN. TGF-β1 is induced by hyperplycemia, AGE, Ang II, and reactive oxygen species (ROS). Additionally, our laboratory have shown that both EGF (epidermal growth factor) and EGF receptor (EGFR) are overexpressed in DN rats. Thus, we wished to understand the role of EGFR in an in vitro model of DN. We found that TGF-β1 phosphorylated EGFR and up-regulated EGFR mRNA and protein expression in NRK-49F cells. TGF-β1 also induced FGF-2 and PAI-1 expression via inducing p-EGFR. Inhibition of EGFR (Iressa) or Smad2/3 (by SB-431542 and Smad2、Smad3 dominant negative plasmid) attenuated TGF-β1-induced FGF-2 and PAI-1 expression. Thus, TGF-β1 induced FGF-2 and PAI-1 expression via EGFR and Smad2/3. Inhibiting EGFR also attenuated cell cycle change. Moreover, TGF-β1-inducd proliferation is accompanied by p38 and ERK phosphorylation. We found that TGF-β1 actived EGFR-ERK signaling to induce cell proliferation. Morevoer, hyperglycemia (HG) and Ang II induced TGF-β1 and collagen synthesis and induced cell proliferation. Thus, TGF-β1 activated EGFR signaling through Smad2/3. Moreover, TGF-β1 induced FGF-2 and PAI-1 expression. FGF-2 induced extracellular matrix expression whereas PAI-1 decreases extracellular matrix degradation thereby inducing fibrosis. Iressa reversed TGF-β1-induced fibrosis and proliferation in NRK-49F cells. Thus, EGFR is involved in the pathogenesis of DN in this in vitro model.