Role of the EGF Receptor in Diabetic Nephropathy

描述（由申请人提供）： 本项目的总体目标是确定表皮生长因子受体（EGFR）在糖尿病肾病发生和进展中的作用。我们最近关于EGFR激活在糖尿病肾病中的作用的令人兴奋的发现为我们提出的研究奠定了基础。EGFR在肾脏的肾小球和肾小管中均表达，我们最近的研究表明EGFR活化与慢性肾脏疾病中肾小球病和肾小管间质纤维化的发展有关。我们已经发现血管紧张素II、EGFR和TGF-β在进行性肾脏疾病中的新的相互作用。在长期暴露于血管紧张素II的小鼠中，肾小管中的EGFR活化增加。引人注目的是，在用选择性EGFR酪氨酸激酶抑制剂厄洛替尼治疗的小鼠中，或在近端小管中选择性缺失的floxed EGFR小鼠中，在暴露于慢性血管紧张素II输注的野生型小鼠中观察到的进行性肾小管间质纤维化的显著抑制。更令人惊讶的是，当EGFR表达或活化被抑制时，血管紧张素II输注引起的TGF-β表达和Smad 2/3活化的增加几乎完全被阻止。此外，我们的初步结果表明，在糖尿病小鼠模型中，肾小球和肾小管中存在持续的肾脏EGFR活化，并且当EGFR表达或活化被阻断时，肾脏中糖尿病诱导的TGF-β表达和受体活化的增加被抑制。我们还发现EGFR配体HB-EGF的肾小球和小动脉表达增加。我们的初步结果表明，无论是基因或药物抑制EGFR信号显着减缓糖尿病肾病的进展，在小鼠模型的糖尿病。因此，这项资助的首要目的是确定EGFR和/或EGFR信号通路是否可能成为治疗糖尿病肾损伤的潜在治疗靶点。我们将针对EGFR信号传导在糖尿病性肾小球病和肾小管间质损伤的发展和进展中的作用，具体目标如下：目标#1）表征EGFR持续活化在糖尿病性肾小球和肾小管损伤中的作用确定持续EGFR活化介导肾小球损伤的机制以及抑制EGFR表达或活化对糖尿病肾小球病发展的影响;确定糖尿病肾病中肾小球中异常EGFR活化的潜在机制;和确定糖尿病肾病中近端小管EGFR活化介导进行性肾小管间质损伤的机制）和目的#2）鉴定在糖尿病肾病的发展和进展中起有害作用的EGFR信号传导途径。

DESCRIPTION (provided by applicant): The overall goal of this project is to determine the role of the epidermal growth factor receptor (EGFR) in the development and progression of diabetic nephropathy. Our exciting recent discoveries concerning the role of EGFR activation in diabetic nephropathy form the basis for our proposed studies. EGFR is expressed in both glomeruli and tubules in the kidney, and our recent studies implicate EGFR activation in development of both glomerulopathy and tubulointerstitial fibrosis in chronic kidney disease. We have found novel interactions of angiotensin II, EGFR and TGF-ss in progressive kidney disease. In mice subjected to chronic angiotensin II exposure, there is increased EGFR activation in kidney tubules. Strikingly, in mice treated with the selective EGFR tyrosine kinase inhibitor, erlotinib, or in floxed EGFR mice with selective deletion in proximal tubules, there is marked inhibition of the progressive tubulointerstitial fibrosis seen in the wild type mice exposed to the chronic angiotensin II infusion. Even more strikingly, the increased TGF-ss expression and Smad2/3 activation that occur in response to angiotensin II infusion are almost completely prevented when EGFR expression or activation is inhibited. Furthermore, our preliminary results indicate that there is persistent renal EGFR activation in mouse models of diabetes both in glomeruli and in tubules, and the increased diabetes-induced TGF-ss expression and receptor activation in the kidney are inhibited when EGFR expression or activation is blocked. We have also found increased glomerular and arteriolar expression of the EGFR ligand, HB-EGF. Our preliminary results indicate that either genetic or pharmacologic inhibition of EGFR signaling markedly slows the progression of diabetic nephropathy in murine models of diabetes. Therefore, the overriding aim of this grant is to determine whether EGFR and/or EGFR signaling pathways could be potential therapeutic targets for the treatment of diabetic kidney injury. We will address the role of the EGFR signaling in development and progression of diabetic glomerulopathy and tubulointerstitial injury in the following specific aims: Aim #1) Characterize the Role of Persistet EGFR Activation in Diabetic Glomerular and Tubular Injury (Determining mechanisms by which persistent EGFR activation mediates glomerular injury and the effects of inhibition of EGFR expression or activation on development of diabetic glomerulopathy; determining mechanisms underlying aberrant EGFR activation in the glomerulus in diabetic nephropathy; and determining mechanisms by which proximal tubule EGFR activation mediates progressive tubulointerstitial injury in diabetic nephropathy) and Aim #2) Identify the EGFR signaling pathways that play a deleterious role in development and progression of diabetic nephropathy.