Inhibition of the epidermal growth factor receptor preserves podocytes and attenuates albuminuria in experimental diabetic nephropathy
Inhibition of the epidermal growth factor receptor preserves podocytes and attenuates albuminuria in experimental diabetic nephropathy
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DOI：
10.1111/j.1440-1797.2011.01451.x
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发表时间：
2011-08-01
期刊：
影响因子：
2.5
通讯作者：
Kelly, Darren J.
中科院分区：
文献类型：
--
作者：
Advani, Andrew;Wiggins, Kathryn J.;Kelly, Darren J.
目的：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)-EGF 受体 (EGFR) 系统在介导肾脏肥大中发挥着关键作用，它可以调节细胞生长和增殖，并通过 EGFR 的反式激活介导血管紧张素 II 的作用。在本研究中，我们试图在以血管紧张素 II 依赖性高血压为特征的糖尿病实验模型中研究长期抑制 EGFR 酪氨酸激酶的效果。方法：雌性杂合链脲佐菌素糖尿病 TGR(mRen-2)27 大鼠接受 EGFR 抑制剂 PKI 166 每日口服给药，持续 16 周。 TGR(mRen-2) 27 只具有 PKI 166 的大鼠可减轻糖尿病引起的肾脏大小增加、肾小球肥大和白蛋白尿。在糖尿病 TGR(mRen-2) 27 大鼠中，通过 EGFR 抑制，白蛋白尿的减少与足细胞核标记物 WT1 呈阳性染色的肾小球细胞数量的保留有关。 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) 的药物相比，EGFR 抑制对糖尿病动物的系膜基质的数量或肾小管损伤的程度没有影响。结论：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的增大，这与足细胞的保留和足细胞的减少有关。 糖尿病中的蛋白尿。因此，针对 EGF-EGFR 通路可能代表了对于 RAS 阻断后病情仍持续进展的患者的一种治疗策略。
Aim: 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.Methods: Female heterozygous streptozotocin-diabetic TGR(mRen-2)27 rats were treated with the EGFR inhibitor PKI 166 by daily oral dosing for 16 weeks.Results: 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.Conclusion: 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.