Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis

Abstract

Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of diabetic nephropathy and renal fibrosis; however, the causative role of sustained EGFR activation is unclear. Here, we generated a novel kidney fibrotic mouse model of persistent EGFR activation by selectively expressing the EGFR ligand, human heparin-binding EGF-like growth factor (hHB-EGF), in renal proximal tubule epithelium. hHB-EGF expression increased tyrosine kinase phosphorylation of EGFR and the subsequent activation of downstream signaling pathways, including ERK and AKT, as well as the profibrotic TGF-β1/SMAD pathway. Epithelial-specific activation of EGFR was sufficient to promote spontaneous and progressive renal tubulointerstitial fibrosis, as characterized by increased collagen deposition, immune cell infiltration, and α-smooth muscle actin (α-SMA)-positive myofibroblasts. Tubule-specific EGFR activation promoted epithelial dedifferentiation and cell-cycle arrest. Furthermore, EGFR activation in epithelial cells promoted the proliferation of α-SMA myofibroblasts in a paracrine manner. Genetic or pharmacologic inhibition of EGFR tyrosine kinase activity or downstream MEK activity attenuated the fibrotic phenotype. This study provides definitive evidence that sustained activation of EGFR in proximal epithelia is sufficient to cause spontaneous, progressive renal tubulointerstitial fibrosis, evident by epithelial dedifferentiation, increased myofibroblasts, immune cell infiltration, and increased matrix deposition.-Overstreet, J. M., Wang, Y., Wang, X., Niu, A., Gewin, L. S., Yao, B., Harris, R. C., Zhang, M.-Z. Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis.

Noninvasive quantitative magnetization transfer MRI reveals tubulointerstitial fibrosis in murine kidney

“…In the hHB-EGF Tg/Tg model, renal tubulointerstitial fibrosis develops by 6 weeks of age and its level increases longitudinally as the mouse ages. 6 The hHB-EGF Tg/Tg mice at 16 weeks showed evident increments in tPSR-detected regions compared with normal WT mice ( Figure 5). The sensitivity and specificity of tPSR were the highest to fibrosis among the MRI parameters in this study ( Figure 6 and Table 3).…”

“…In hHB-EGF Tg/Tg mice, the contrasts in some derived parametric maps were unlike those observed in normal WT mice ( Figure 2), consistent with the associated pathologic changes. 6 The characteristic PSR map of hHB-EGF Tg/Tg kidney shows scattered clusters of abnormally high PSR values (indicated by the arrow in Figure 2B) located in the OSOM (the conjunction between cortex and ISOM). The MTR maps were also compared between WT and hHB-EGF Tg/Tg kidneys, but they were not significantly different ( Figure 2).…”

“…10,28,30,31 Previous histologic studies of hHB-EGF Tg/Tg progression also revealed these abnormal features in the OSOM of kidneys. 6 We compared the changes of mPSR in CR + OSOM and tPSR-detected fibrotic areas (%) with histological fibrosis indices between WT and hHB-EGF Tg/Tg kidneys ( Figure 7B). Twelve WT and eight hHB-EGF Tg/Tg kidneys with both MRI and histological results were included in the comparison.…”

Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation

“…CCN2 has been shown to be involved in several proliferative disorders [5][6][7][8][9][10]. Several EGFR ligands, such as epidermal growth factor (EGF), heparin-binding EGF, epiregulin, and CCN2, can induce proliferation, migration and invasion of epithelial cells and fibroblasts [44,[56][57][58][59]. Now, we have found that CCN2, via EGFR signalling activation, can regulate cell proliferation in the kidney, as demonstrated by the increased number of PCNA-positive proliferating cells.…”

Anti‐fibrotic effects of synthetic TGF‐β1 and Smad oligodeoxynucleotide on kidney fibrosis in vivo and in vitro through inhibition of both epithelial dedifferentiation and endothelial‐mesenchymal transitions

“…TGF-β1 binds to type II receptors, which then recruits and activates type I receptors to shape a heteromeric TGF-β1 receptor complex. 23,24 Antisense oligodeoxynucleotide (ODN) containing the target mRNA sequence has been developed as a promising strategy to modulate targeted gene deletion through hybridization with Mrna. The phosphorylated Smad2/3 combines with Smad4, and this complex translocates to the nucleus and controls fibrotic gene expression.…”