Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Nephrology (Carlton). 2011 Aug;16(6):573-81. doi: 10.1111/j.1440-1797.2011.01451.x.
Early renal enlargement may predict the future development of nephropathy in patients with diabetes. The epidermal growth factor (EGF)-EGF receptor (EGFR) system plays a pivotal role in mediating renal hypertrophy, where it may act to regulate cell growth and proliferation and also to mediate the actions of angiotensin II through transactivation of the EGFR. In the present study we sought to investigate the effects of long-term inhibition of the EGFR tyrosine kinase in an experimental model of diabetes that is characterized by angiotensin II dependent hypertension.
Female heterozygous streptozotocin-diabetic TGR(mRen-2)27 rats were treated with the EGFR inhibitor PKI 166 by daily oral dosing for 16 weeks.
Treatment of TGR(mRen-2)27 rats with PKI 166 attenuated the increase in kidney size, glomerular hypertrophy and albuminuria that occurred with diabetes. The reduction in albuminuria, with EGFR inhibition in diabetic TGR(mRen-2)27 rats, was associated with preservation of the number of glomerular cells staining positively for the podocyte nuclear marker, WT1. Immunostaining for WT1 inversely correlated with glomerular volume in diabetic rats. In contrast to agents that block the renin-angiotensin system (RAS), EGFR inhibition had no effect on either the quantity of mesangial matrix or the magnitude of tubular injury in diabetic animals.
These observations indicate that inhibition of the tyrosine kinase activity of the EGFR attenuates kidney and glomerular enlargement in association with podocyte preservation and reduction in albuminuria in diabetes. Accordingly, targeting the EGF-EGFR pathway may represent a therapeutic strategy for patients who continue to progress despite RAS-blockade.
早期肾脏增大可能预测糖尿病患者肾病的未来发展。表皮生长因子（EGF）-表皮生长因子受体（EGFR）系统在介导肾肥大中起关键作用，它可能通过 EGFR 的转激活来调节细胞生长和增殖，并介导血管紧张素 II 的作用。在本研究中，我们试图研究在以血管紧张素 II 依赖性高血压为特征的糖尿病实验模型中，长期抑制 EGFR 酪氨酸激酶的作用。
雌性杂合链脲佐菌素-糖尿病 TGR(mRen-2)27 大鼠每天口服给予 EGFR 抑制剂 PKI 166 治疗 16 周。
PKI 166 治疗 TGR(mRen-2)27 大鼠可减轻糖尿病大鼠肾脏增大、肾小球肥大和白蛋白尿增加。在糖尿病 TGR(mRen-2)27 大鼠中，EGFR 抑制导致白蛋白尿减少，与足细胞核标记物 WT1 阳性肾小球细胞数量的保存有关。WT1 的免疫染色与糖尿病大鼠的肾小球体积呈负相关。与阻断肾素-血管紧张素系统（RAS）的药物相反，EGFR 抑制对糖尿病动物的系膜基质量或肾小管损伤的程度均无影响。
这些观察结果表明，抑制 EGFR 的酪氨酸激酶活性可减轻肾脏和肾小球增大，同时保留足细胞并减少糖尿病中的白蛋白尿。因此，针对 EGF-EGFR 途径可能代表一种治疗策略，适用于尽管进行了 RAS 阻断但仍继续进展的患者。
