EGF receptor deletion in podocytes attenuates diabetic nephropathy.
Authors Chen J, Chen JK, Harris RC
Submitted By Raymond Harris on 5/10/2015
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2015
Date Published 5/1/2015
Volume : Pages 26 : 1115 - 1125
PubMed Reference 25185988
Abstract The generation of reactive oxygen species (ROS), particularly superoxide, by
damaged or dysfunctional mitochondria has been postulated to be an initiating
event in the development of diabetes complications. The glomerulus is a primary
site of diabetic injury, and podocyte injury is a classic hallmark of diabetic
glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific
EGF receptor (EGFR) knockout mice (EGFR(podKO)) and their wild-type (WT)
littermates had similar levels of hyperglycemia and polyuria, but EGFR(podKO)
mice had significantly less albuminuria and less podocyte loss compared with WT
diabetic mice. Furthermore, EGFR(podKO) diabetic mice had less TGF-ß1
expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition.
Immunoblotting of isolated glomerular lysates revealed that the upregulation of
cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated
in EGFR(podKO) diabetic mice. Administration of the SOD mimetic mito-tempol or
the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src,
p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-ß1 expression and prevented the alteration
of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice.
High-glucose treatment of cultured mouse podocytes induced similar alterations
in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and
expression of TGF-ß1, cleaved caspase 3, and Bcl2. These alterations were
inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR
expression or activity. Thus, results of our studies utilizing mice with
podocyte-specific EGFR deletion demonstrate that EGFR activation has a major
role in activating pathways that mediate podocyte injury and loss in diabetic

Investigators with authorship
Raymond HarrisVanderbilt University