Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats

Torres, Vicente E.; Sweeney, William E.; Wang, Xiaofang; Qian, Qi; Harris, Peter C.; Frost, Philip; Avner, Ellis D.

doi:10.1111/j.1523-1755.2004.00952.x

Cited by 69 publications

(52 citation statements)

References 56 publications

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“…25 VPV2R and cAMP levels are elevated in the kidneys of PCK rats. 26 In addition, EGFR tyrosine kinase inhibition had no beneficial effect on the PKD of the PCK rat in our experiments as well as in those reported by others. 26 Therefore, the expression of p-ERK1/2 in the kidney cyst lining epithelial cells of the PCK rat may be associated with the cAMP pathway, not with the EGF/ TGF-␣/EGFR pathway.…”

Section: Discussionsupporting

confidence: 70%

“…Recent studies showed that treatment of the PCK rat with EGFR tyrosine kinase inhibitors, EKI-785 and EKB-569, led to mild, but not significant, improvement in the liver cyst volume. 26 In this study, p-EGFR was undetectable in the liver after gefitinib treatment, but immunostaining showed that p-ERK1/2 was persistently expressed in the BECs of PCK rats after treatment. Although a number of studies have implicated the importance of the EGF/TGF-␣/EGFR pathway in the pathogenesis of PKD, the proliferation of cholangiocytes seems not to be simply mediated by this pathway.…”

Section: Discussionmentioning

confidence: 93%

“…Inhibition of PKD of the PCK rat by the use of EGFR tyrosine kinase inhibitors (EKI-785 and EKB-569) resulted in no effect or a worsened PKD as well as no significant effect on the fibrocystic liver disease. 26 EGFR tyrosine kinase activation triggers numerous downstream signaling pathways, such as the extracellular-regulated protein kinase (ERK)/mitogen-activated protein kinase (MAPK), and the phosphoinositide-3-kinase (PI3K)/Akt pathways. 27 Recently, we demonstrated that biliary epithelial cells (BECs) isolated from the PCK rat were hyperreactive to EGF, which was accompanied by the activation of the MAPK pathway consisting of MAPK/ERK kinase 5 (MEK5)/ERK5 in vitro.…”

mentioning

confidence: 99%

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Inhibition of Intrahepatic Bile Duct Dilation of the Polycystic Kidney Rat with a Novel Tyrosine Kinase Inhibitor Gefitinib

Sato

Harada

Furubo

et al. 2006

The American Journal of Pathology

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The polycystic kidney (PCK) rat represents a liver and kidney cyst pathology corresponding to Caroli's disease with congenital hepatic fibrosis and autosomal recessive polycystic kidney disease. We previously reported that an epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), significantly inhibited the abnormal growth of biliary epithelial cells of PCK rats in vitro. This study investigated the effects of gefitinib on cyst pathogenesis of the PCK rat both in vitro and in vivo. A three-dimensional culture model of biliary epithelial cells in the collagen gel matrix was used for in vitro analysis. For in vivo experiments, PCK and control rats were treated with gefitinib between 3 and 10 weeks of age. In vitro, gefitinib had strong inhibitory effects on biliary cyst formation of PCK rats. In vivo, treatment with gefitinib significantly inhibited the cystic dilatation of the intrahepatic bile ducts of PCK rats, which was accompanied by improvement of liver fibrosis. By contrast, no beneficial effects were observed on renal cyst development because of the treatment. These results suggest that signaling pathways mediated by epidermal growth factor receptor are involved in biliary dysgenesis of the PCK rat, with the mechanisms of cyst progression being different between the liver and kidney.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

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Inhibition of Intrahepatic Bile Duct Dilation of the Polycystic Kidney Rat with a Novel Tyrosine Kinase Inhibitor Gefitinib

Sato

Harada

Furubo

et al. 2006

The American Journal of Pathology

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“…57 Treatment with EGFR tyrosine kinase inhibitors inhibits renal cyst growth in several PKD rodent models, 58,59 but not all. 60 The EGFR and Src interact with each other, Src can phosphorylate multiple tyrosine residues of the EGFR, and both kinases are thought to be able to mutually activate each other. 61 STAT3 activation in response to EGFR signaling requires Src.…”

Section: Discussionmentioning

confidence: 99%

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Talbot¹,

Song²,

Wang³

et al. 2014

Journal of the American Society of Nephrology

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Polycystin-1 (PC1) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease (ADPKD). The transcription factor STAT3 (signal transducer and activator of transcription 3) was shown to be activated in cyst-lining cells in ADPKD and PKD mouse models and may drive renal cyst growth, but the mechanisms leading to persistent STAT3 activation are unknown. A proteolytic fragment of PC1 corresponding to the cytoplasmic tail, PC1-p30, is overexpressed in ADPKD. Here, we show that PC1-p30 interacts with the nonreceptor tyrosine kinase Src, resulting in Srcdependent activation of STAT3 by tyrosine phosphorylation. The PC1-p30-mediated activation of Src/ STAT3 was independent of JAK family kinases and insensitive to the STAT3 inhibitor suppressor of cytokine signaling 3. Signaling by the EGF receptor (EGFR) or cAMP amplified the activation of Src/STAT3 by PC1-p30. Expression of PC1-p30 changed the cellular response to cAMP signaling. In the absence of PC1-p30, cAMP dampened EGFR-or IL-6-dependent activation of STAT3; in the presence of PC1-p30, cAMP amplified Src-dependent activation of STAT3. In the polycystic kidney (PCK) rat model, activation of STAT3 in renal cystic cells depended on vasopressin receptor 2 (V2R) signaling, which increased cAMP levels. Genetic inhibition of vasopressin expression or treatment with a pharmacologic V2R inhibitor strongly suppressed STAT3 activation and reduced renal cyst growth. These results suggest that PC1, via its cleaved cytoplasmic tail, integrates signaling inputs from EGFR and cAMP, resulting in Src-dependent activation of STAT3 and a proliferative response.

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“…For renal cAMP estimations, a cAMP ELISA system without acetylation (Biomedical Technologies, Stoughton, MA) was used. Results from both assays were expressed per wet weight of tissue (15,35).…”

Section: Elisa Of Et-1 and Campmentioning

confidence: 99%

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

Chang¹,

Parker²,

Nahas³

et al. 2007

Journal of the American Society of Nephrology

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease that causes kidney failure and accounts for 10% of all patients who are on renal replacement therapy. However, the marked phenotypic variation between patients who carry the same PKD1 or PKD2 mutation suggests that nonallelic factors may have a greater influence on the cystic phenotype. Endothelin-1 (ET-1) transgenic mice have been reported to develop profound renal cystic disease and interstitial fibrosis without hypertension. The hypothesis that ET-1 acts as a modifying factor for cystic disease progression was tested in an orthologous mouse model of ADPKD (Pkd2 WS25/؊ ). Four experimental groups (n ‫؍‬ 8 to 11) were treated from 5 to 16 wk of age with the highly selective orally active receptor antagonists ABT-627 (ETA) and A-192621 (ETB) singly or in combination. Unexpected, ETB blockade led to accelerated cystic kidney disease. Of significance, this was associated with a reduction in urine volume and sodium excretion and increases in urine osmolarity and renal cAMP and ET-1 concentrations. The deleterious effect of chronic ETB blockade was neutralized by simultaneous ETA blockade. ETA blockade alone resulted in a significant increase in tubular cell proliferation but did not alter the cystic phenotype. It is concluded that the balance between ETA and ETB signaling is critical for maintaining tubular structure and function in the cystic kidney. These results implicate ET, acting via vasopressin-dependent and independent pathways, as a major modifying factor for cystic disease progression in human ADPKD. A utosomal dominant polycystic kidney disease (AD-PKD) causes kidney failure in 10% of all patients who are on renal replacement therapy and is caused by mutations in PKD1 or PKD2 (1). The ADPKD proteins polycystin-1 and polycystin-2 function as a complex and regulate multiple signaling pathways to maintain normal tubular structure and function (2). Although a weak phenotype-genotype correlation for renal survival has been reported for PKD1, it is apparent that nonallelic factors such as genetic modifying loci and/or environmental factors have a greater influence on the cystic phenotype (3,4). These factors probably account for the marked intrafamilial phenotypic variability that sometimes is seen in PKD1 or PKD2 pedigrees (5,6).The endothelins (ET-1, ET-2, and ET-3) are a family of multifunctional peptides with potent effects on BP, renal function, and cellular behavior. Although ET-1 originally was purified as a highly potent endothelial-derived vasoconstrictor (7), many other cell types, especially in the kidney, can synthesize and bind ET-1, suggesting a range of other functions (8,9). Two ET receptor subtypes, ETA and ETB, have been shown to mediate ET-1 action but often with opposing effects (10,11). During development, ET-1 (acting via ETA receptors) and ET-3 (acting via ETB receptors) are essential for the development of neural crest-derived tissues (12,13).Several lines of evidence had suggested that ET-1 might pa...

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Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats

Cited by 69 publications

References 56 publications

Inhibition of Intrahepatic Bile Duct Dilation of the Polycystic Kidney Rat with a Novel Tyrosine Kinase Inhibitor Gefitinib

Inhibition of Intrahepatic Bile Duct Dilation of the Polycystic Kidney Rat with a Novel Tyrosine Kinase Inhibitor Gefitinib

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease

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