EGF receptor deletion in podocytes attenuates diabetic nephropathy

Jianchun Chen, Jian Kang Chen, Raymond C. Harris

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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 (EGFRpodKO) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFRpodKO mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFRpodKO 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 EGFRpodKO 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.

Original languageEnglish (US)
Pages (from-to)1115-1125
Number of pages11
JournalJournal of the American Society of Nephrology
Volume26
Issue number5
DOIs
StatePublished - May 1 2015

ASJC Scopus subject areas

  • Nephrology

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