Epidermal growth factor receptor expression in human renal allograft biopsies: an immunohistochemical study

Sis, B.; Sarıoğlu, Sülen; Celik, Ali; Zeybel, Müjdat; Soylu, Alper; Bora, Seymen

doi:10.1016/j.trim.2004.05.001

Cited by 17 publications

(19 citation statements)

References 11 publications

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“…There is growing evidence of the role of the EGFR pathway in various types of renal lesions. Increased EGFR activation and expression have been correlated with interstitial fibrosis and tubular atrophy in human renal allograft biopsies (Sis et al, 2004). EGFR activation is involved in endothelin-induced renal vascular and glomerular fibrosis (Francois et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis

Qian

Peng

Qiu

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Chronic activation of renin-angiotensin system (RAS) greatly contributes to renal fibrosis and accelerates the progression of chronic kidney disease; however, the underlying molecular mechanism is poorly understood. Angiotensin II (Ang II), the central component of RAS, is a key regulator of renal fibrogenic destruction. Here we show that epidermal growth factor receptor (EGFR) plays an important role in Ang II-induced renal fibrosis. Inhibition of EGFR activation by novel small molecules or by short hairpin RNA knockdown in Ang II-treated SV40 mesangial cells in vitro suppresses protein kinase B and extracellular signal-related kinase signaling pathways and transforming growth factor-b/Sma-and Mad-related protein activation, and abolishes the accumulation of fibrotic markers such as connective tissue growth factor, collagen IV. The transactivation of EGFR by Ang II in SV40 cells depends on the phosphorylation of proto-oncogene tyrosine-protein kinase Src (c-Src) kinase. Further validation in vivo demonstrates that EGFR small molecule inhibitor successfully attenuates renal fibrosis and kidney dysfunction in a mouse model induced by Ang II infusion. These findings indicate a crucial role of EGFR in Ang II-dependent renal deterioration, and reveal EGFR inhibition as a new therapeutic strategy for preventing progression of chronic renal diseases.

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Section: Discussionmentioning

confidence: 99%

Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis

Qian

Peng

Qiu

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Increased EGFR activation and expression was correlated with interstitial fibrosis and tubular atrophy in human renal allograft biopsies. 36 EGFR activation is involved in endothelininduced renal vascular and glomerular fibrosis. 37 Furthermore, interstitial fibrosis and tubular atrophy from prolonged ischemia and chronic infusion of angiotensin II were associated with increased EGFR activity.…”

Section: Discussionmentioning

confidence: 99%

Genetic or Pharmacologic Blockade of EGFR Inhibits Renal Fibrosis

Liu

Guo

Pang

et al. 2012

Journal of the American Society of Nephrology

142

144

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Although enhanced activation of the EGF receptor (EGFR) associates with the development and progression of renal fibrosis, the mechanisms linking these observations are not completely understood. Here, after unilateral ureteral obstruction (UUO), wild-type mice exhibited sustained EGFR phosphorylation in the kidney and developed renal fibrosis that was more severe than the renal fibrosis observed in waved-2 mice, which have reduced EGFR tyrosine kinase activity. Waved-2 mice also showed fewer renal tubular cells arrested at G2/M, reduced expression of a-smooth muscle actin (a-SMA), downregulation of multiple genes encoding profibrogenic cytokines, including TGF-b1, and dephosphorylation of Smad3, STAT3, and ERK1/2. Administration of the specific EGFR inhibitor gefitinib recapitulated this phenotype in wild-type mice after UUO. Furthermore, inactivation of either EGFR or STAT3 reduced UUO-induced expression of lipocalin-2, a molecule associated with the pathogenesis of CKD. In cultured renal interstitial fibroblasts, inhibition of EGFR also abrogated TGF-b1-or serum-induced phosphorylation of EGFR, STAT3, ERK1/2, and Smad3 as well as expression of a-SMA and extracelluar matrix proteins. Taken together, these data suggest that EGFR may mediate renal fibrogenesis by promoting transition of renal epithelial cells to a profibrotic phenotype, increased production of inflammatory factors, and activation of renal interstitial fibroblasts. Inhibition of EGFR may have therapeutic potential for fibrotic kidney disease.

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“…Chronic allograft nephropathy is the predominant cause of late allo graft loss 71 , and is characterized by interstitial fibro sis, chronic inflammation, arteriosclerosis and tubular and glomerular lesions 72 . EGFR expression has been demonstrated in human renal allograft biopsies 73 , and in rats, the renal expression of EGF and the EGFR are increased by day 5 after kidney transplantation. In addition, erlotinib -an orally administered tyro sine kinase inhibitor (TKI) that functions as an EGFR inhibitor -prevented chronic allograft rejection and maintained better allograft function than did the immunosuppressant ciclosporin in this kidney transplantation model 71 .…”

Section: Nature Reviews | Nephrologymentioning

confidence: 99%

The epidermal growth factor receptor pathway in chronic kidney diseases

et al. 2016

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The epidermal growth factor receptor (EGFR) pathway has a critical role in renal development, tissue repair and electrolyte handling. Numerous studies have reported an association between dysregulation of this pathway and the initiation and progression of various chronic kidney diseases such as diabetic nephropathy, chronic allograft nephropathy and polycystic kidney disease through the promotion of renal cell proliferation, fibrosis and inflammation. In the oncological setting, compounds that target the EGFR pathway are already in clinical use or have been evaluated in clinical trials; in the renal setting, therapeutic interventions targeting this pathway by decreasing ligand availability with disintegrin and metalloproteinase inhibitors or with ligand-neutralizing antibodies, or by inhibiting receptor activation with tyrosine kinase inhibitors or monoclonal antibodies are only just starting to be explored in animal models of chronic kidney disease and in patients with autosomal dominant polycystic kidney disease. In this Review we focus on the role of the EGFR signalling pathway in the kidney under physiological conditions and during the pathophysiology of chronic kidney diseases and explore the clinical potential of interventions in this pathway to treat chronic renal diseases.

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Epidermal growth factor receptor expression in human renal allograft biopsies: an immunohistochemical study

Cited by 17 publications

References 11 publications

Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis

Novel Epidermal Growth Factor Receptor Inhibitor Attenuates Angiotensin II-Induced Kidney Fibrosis

Genetic or Pharmacologic Blockade of EGFR Inhibits Renal Fibrosis

The epidermal growth factor receptor pathway in chronic kidney diseases

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