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-b1 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-b1 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-b1, 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.

Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1

“…3, D-F). We also observed glomerular up-regulation of the EGFR heterodimerization partner of ErbB4 in these samples, confirming similar findings by others (47)(48)(49)(50). Co-staining with podocyte marker synaptopodin showed that the increase in their expression co-localized within podocytes in the glomeruli.…”

“…The results presented here suggest that both proteins are induced in the diabetic glomeruli. Similarly, the pan-ErbB kinase inhibitor erlotinib binds to EGFR with a significantly higher affinity (2 nM) than ErbB4 (55) and has been shown to protect against DN (47)(48)(49)(50), which might suggest that the efficacy of erlotinib observed here is likely due to its inhibition of EGFR over ErbB4, suggesting that EGFR is the main culprit in disease pathogenesis. However, here we find that, at least with the TGF-␤1 treatment of podocytes in vitro, ErbB4 levels increased in cells without affecting levels of EGFR, suggesting that ErbB4 up-regulation has pathogenic relevance.…”

“…Prior studies have also shown that EGFR phosphorylation and activation in podocytes promotes glomerular injury in response to inflammatory and diabetic stimuli, and that its pharmacologic blockade or podocyte-specific deletion is protective (47)(48)(49)(50). EGFR phosphorylation leads to induction of TGF␤-Smad-2/3 signaling, resulting in podocyte apoptosis.…”

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

“…The increased production of ROS plays a key role in the development and progression of DN [23] . Oxidative stress occurs when ROS affect the balance between oxidative pressure and antioxidant defense.…”

Interaction of the EGF Receptor and the Hippo Pathway in the Diabetic Kidney

“…10 Studies by us and others have found that prolonged EGFR activation in diabetic animals mediated aberrant activation of a TGF-b1-smad signaling pathway, and inhibition of EGFR signaling in diabetic kidney by pharmacologic or genetic strategies markedly preserved renal function and slowed DN progression. [11][12][13][14] The elucidation of the role of the Hippo pathway, which is conserved from Drosophila to mammals, has provided new insights in understanding the regulation of cell proliferation, cell death, and cell differentiation to control organ size. The core components of the Hippo signaling pathway-Warts, Salvador, Hippo, and Mats-were discovered in genetic screens in Drosophila for tumor suppressor genes.…”