Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China.
J Am Soc Nephrol. 2012 May;23(5):854-67. doi: 10.1681/ASN.2011050493. Epub 2012 Feb 23.
Although enhanced activation of the EGF receptor (EGFR) associates with the development and progression of renal fibrosis, the mechanisms linking these observations are not completely understood. Here, after unilateral ureteral obstruction (UUO), wild-type mice exhibited sustained EGFR phosphorylation in the kidney and developed renal fibrosis that was more severe than the renal fibrosis observed in waved-2 mice, which have reduced EGFR tyrosine kinase activity. Waved-2 mice also showed fewer renal tubular cells arrested at G2/M, reduced expression of α-smooth muscle actin (α-SMA), downregulation of multiple genes encoding profibrogenic cytokines, including TGF-β1, and dephosphorylation of Smad3, STAT3, and ERK1/2. Administration of the specific EGFR inhibitor gefitinib recapitulated this phenotype in wild-type mice after UUO. Furthermore, inactivation of either EGFR or STAT3 reduced UUO-induced expression of lipocalin-2, a molecule associated with the pathogenesis of CKD. In cultured renal interstitial fibroblasts, inhibition of EGFR also abrogated TGF-β1- or serum-induced phosphorylation of EGFR, STAT3, ERK1/2, and Smad3 as well as expression of α-SMA and extracelluar matrix proteins. Taken together, these data suggest that EGFR may mediate renal fibrogenesis by promoting transition of renal epithelial cells to a profibrotic phenotype, increased production of inflammatory factors, and activation of renal interstitial fibroblasts. Inhibition of EGFR may have therapeutic potential for fibrotic kidney disease.
虽然表皮生长因子受体（EGFR）的激活增强与肾纤维化的发生和进展有关，但将这些观察结果联系起来的机制尚不完全清楚。在这里，在单侧输尿管梗阻（UUO）后，野生型小鼠的肾脏中持续存在 EGFR 磷酸化，并发生比 waved-2 小鼠更严重的肾纤维化，waved-2 小鼠的 EGFR 酪氨酸激酶活性降低。waved-2 小鼠的肾小管细胞在 G2/M 期停滞的数量也较少，α-平滑肌肌动蛋白（α-SMA）的表达减少，编码促纤维化细胞因子的多个基因（包括 TGF-β1）的表达下调，Smad3、STAT3 和 ERK1/2 的磷酸化减少。在 UUO 后，特异性 EGFR 抑制剂吉非替尼在野生型小鼠中再现了这种表型。此外，EGFR 或 STAT3 的失活减少了 UUO 诱导的脂联素-2 的表达，脂联素-2 是与 CKD 发病机制相关的分子。在培养的肾间质成纤维细胞中，EGFR 的抑制也消除了 TGF-β1 或血清诱导的 EGFR、STAT3、ERK1/2 和 Smad3 的磷酸化以及α-SMA 和细胞外基质蛋白的表达。总之，这些数据表明，EGFR 可能通过促进肾小管上皮细胞向促纤维化表型的转化、增加炎症因子的产生和激活肾间质成纤维细胞来介导肾纤维化。EGFR 的抑制可能对纤维性肾病具有治疗潜力。
