Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury

Terzi, Fabiola; Burtin, Martine; Hekmati, Mehrak; Federici, Pierre; Grimber, Giselle; Briand, Pascale; Friedlander, Gérard

doi:10.1172/jci8315

Cited by 165 publications

(154 citation statements)

References 46 publications

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“…NRE cells can be grown in culture for 10 passages and are easily isolated and characterized (Sens et al, 1999;Trifillis, 1999). We characterized NRE cells for cytokeratin expression and tubule-specific gene expression, for example, megalin [(data not shown; (Dedir et al, 1996;Trifillis, 1999;Terzi et al, 2000)]. Thus, we have relevant cell models in which TBR2 and TBR3 expression can be manipulated to examine the impact of TBR biology on human RCC carcinogenesis and progression, in vitro.…”

Section: Tgfb Receptor Expression In Rcc Cell Linesmentioning

confidence: 99%

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

et al. 2003

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Renal cell carcinoma (RCC) is a major health issue. Whereas localized disease can be cured surgically, there is no effective therapy for metastatic disease. The development of an effective therapy will require an understanding of the pathways that are important in RCC carcinogenesis and progression. Using genomic profiling of patientmatched tissue, we have identified aberrations in the transforming growth factor b (TGFb) signaling pathway in RCC. We observed loss of type III TGFb receptor (TBR3) expression in all RCC samples. This suggests that TBR3 loss is an early event in RCC carcinogenesis and plays a sentinel role in the acquisition of a tumorigenic phenotype. We also observed subsequent loss of type II TGFb receptor (TBR2) expression in metastatic RCCs. We propose that loss of TBR3 is necessary for RCC carcinogenesis, and that loss of TBR2 leads to acquisition of a metastatic phenotype. To this end, we have identified a human renal cell carcinoma line (UMRC6) that is representative of localized, nonmetastatic RCC, reflecting a loss of TBR3, but not TBR2 expression. Another cell line, UMRC3, is highly metastatic, having lost TBR3 and TBR2 expression. We demonstrate functional loss of TGFb responsiveness in these cell lines as observed through phenotypic and transcriptional responsiveness to exogenous TGFb. Restoring TBR2 and TBR3 expression in UMRC3 cells attenuates cell proliferation, completely restores TGFb-mediated transcriptional responses, and completely blocks anchorage independent-growth: while restoration of TBR2 partially restores TGFb-mediated signaling. Based on these data, we propose that dysregulation in TGFb signaling, through stepwise loss in receptor expression, plays a prominent role in RCC carcinogenesis and progression. In addition, these studies unequivocably demonstrate a link between loss of TBR3 and a human disease.

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Section: Tgfb Receptor Expression In Rcc Cell Linesmentioning

confidence: 99%

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

et al. 2003

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“…On the one hand, approaches to overexpress EGF in the kidney lead to acceleration of resolution of the tissue damage. On the other hand, EGF-R signalling was shown to play a role in deterioration of the kidney, and introduction of EGF-R mutants into the kidney reduced fibrotic lesions [82]. The protective effects of HGF during acute renal damage have been extensively studied by Azuma et al [83].…”

Section: Connective Tissue Growth Factormentioning

confidence: 99%

ECM homeostasis in renal diseases: a genomic approach

Eikmans

Baelde

Heer

et al. 2003

The Journal of Pathology

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Chronic renal disease is in general histologically accompanied by a vast amount of scar tissue, ie glomerulosclerosis and interstitial fibrosis. Scarring results from excessive accumulation of extracellular matrix (ECM) components, a process driven by a plethora of cytokines and growth factors. Studies in experimental renal disease which target these regulators using gene therapy limit or prevent the development of scarring. This review focuses specifically on the role of transforming growth factor-beta, platelet-derived growth factor, connective tissue growth factor, hepatocyte growth factor, and epidermal growth factor. The results obtained in animal models hold promise for molecular intervention strategies in human renal disease. Microarray technology allows large-scale gene expression profiling in kidney tissue to identify common molecular pathways in a step towards discovery of new drug targets. Molecular techniques are expected to be used for diagnostic and prognostic purposes in nephrological practice to supplement renal biopsy. Several studies already show that molecular techniques might be of use in routine diagnostic practice. Improvement of diagnosis and prediction of outcome in renal patients might lead to more efficient and earlier therapeutic intervention.

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“…EGFR activation promotes renal fibrosis in animal models (8,19,39). Its involvement in this process has been emphasized by the recent demonstration that transactivation of EGFR by TGF-␣ may play a central role in angiotensin II-mediated renal injury (19).…”

Section: Discussionmentioning

confidence: 99%

“…Blockade of EGFR activation with the EGFR-tyrosine kinase inhibitor gefitinib prevented the decline of renal function and the development of fibrosis in a rat model of hypertensive nephrosclerosis (8). Furthermore, in a subtotal nephrectomy model, expression of a dominant negative EGFR in the proximal tubule protected against tubular atrophy and interstitial fibrosis (39).…”

mentioning

confidence: 99%

Soluble HB-EGF induces epithelial-to-mesenchymal transition in inner medullary collecting duct cells by upregulating Snail-2

Smith

Pozzi

Dhawan³

et al. 2009

American Journal of Physiology-Renal Physiology

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Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury

Cited by 165 publications

References 46 publications

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

Genomic profiling identifies alterations in TGFβ signaling through loss of TGFβ receptor expression in human renal cell carcinogenesis and progression

ECM homeostasis in renal diseases: a genomic approach

Soluble HB-EGF induces epithelial-to-mesenchymal transition in inner medullary collecting duct cells by upregulating Snail-2

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