title: EGF receptor deletion in podocytes attenuates diabetic nephropathy.
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-β1 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-β1 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-β1, 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 nephropathy.
authors.affiliation: Department of Veterans Affairs, Nashville, Tennessee; Departments of Medicine and.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departments of Cellular Biology and Anatomy and Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Chen
authors.affiliation: Department of Veterans Affairs, Nashville, Tennessee; Departments of Medicine and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and ray.harris@vanderbilt.edu.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006943:Hyperglycemia / Q000150:complications; D008297:Male; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; C052617:Bcl2 protein, mouse; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019061:src-Family Kinases; D053148:Caspase 3
keywords: NADPH oxidase; TGF-β; apoptosis; chronic diabetic complications; podocyte