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.
Renal complications of diabetes are increasing in frequency and severity in the Veteran population. Although blockade of angiotensin II production or signaling is a mainstay of treatment of patients with diabetic nephropathy, in most patients, blockade of the renin-angiotensin system slows, but does not halt progression of diabetic nephropathy. There is an urgent need to develop additional therapeutic options to treat diabetic kidney disease. The studies in the current proposal should allow identification of the factors and/or pathways involved in fibrosis that will enable us to develop in vivo strategies to ameliorate and/or ideally prevent end stage renal disease and consequent death due to diabetic nephropathy. Thus, it is expected that the studies proposed in this grant will have a significant impact on the health care of our Veterans and make important contributions to the research mission of the VA.