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

Rayego‐Mateos, Sandra; Morgado‐Pascual, José Luis; Rodrigues-Díez, Raúl R.; Rodrigues‐Díez, Raquel; Falke, Lucas L.; Mezzano, Sergio; Ortíz, Alberto; Egido, Jesús; Goldschmeding, Roel; Ruíz-Ortega, Marta

doi:10.1002/path.5007

Cited by 59 publications

(46 citation statements)

References 84 publications

(154 reference statements)

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“…However, in pathological condition, both beneficial and deleterious roles of EGFR have been observed. In progressive kidney disease, fibrotic renal damage seems to be ameliorated by blocking EGFR [17,18]. However, in the AKI model, renal function recovery and tubular regeneration were both significantly delayed when treated with EGFR tyrosine kinase inhibitor or in the setting of EGFR mutation that induces a reduction in receptor tyrosine kinase activity [19,20].…”

Section: Introductionmentioning

confidence: 99%

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population

et al. 2020

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Purpose: Epidermal growth factor (EGF) has been found to be associated with the development and repair mechanisms of several renal diseases. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in EGF or its receptor genes might have an association with end-stage renal disease (ESRD) or acute renal allograft rejection (AR) in a Korean population. Methods: Three-hundred and forty seven recipients of the first renal transplants for ESRD, including 63 AR patients along with 289 healthy adults were included in the study. Five EGF gene SNPs (rs11568835, rs11568943, rs2237051, rs11569017, and rs3756261) and four EGFR gene SNPs (rs1140475, rs2293347, rs1050171, and rs6965469) were analyzed. The genotypes of these SNPs were analyzed using the AxiomTM genome-wide human assay. Statistical analysis was performed using SNPStats and Haploview version 4.2 software. Multiple logistic regression models (codominant, dominant, recessive, and Log-additive) were used to estimate the odds ratio (OR), 95% confidence interval (CI), and P value. Results: One SNP (rs11569017) in the EGF gene showed significant association with ESRD but not with AR. Another SNP (rs11568835) in the EGF gene showed significant association with susceptibility to AR but not with ESRD. One SNP (rs1050171) in the EGFR gene showed significant association with susceptibility to AR but not with ESRD. Conclusion: Our findings suggest that SNPs in the EGF and EGFR gene may be associated with the risk of ESRD and AR development in the Korean population.

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Section: Introductionmentioning

confidence: 99%

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population

et al. 2020

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“…The most significantly dysregulated pathways were identified by median p-value over different node penalties ( Figure 5). Among these, known drivers of renal fibrosis including TGF-β, WNT, and EGFR/ERbB signaling stand out (33)(34)(35) . These processes are significantly over-represented in CARNIVAL, but are not significant in GSEA (results not shown).…”

Section: Inferred Dysregulated Cellular Processes By Carnival Dysregmentioning

confidence: 99%

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

Liu

Trairatphisan

Gjerga

et al. 2019

Preprint

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While gene expression profiling is commonly used to gain an overview of cellular processes, the identification of upstream processes that drive expression changes remains a challenge. To address this issue, we introduce CARNIVAL, a causal network contextualization tool which derives network architectures from gene expression footprints. CARNIVAL (CAusal Reasoning pipeline for Network identification using Integer VALue programming) integrates different sources of prior knowledge including signed and directed protein-protein interactions, transcription factor targets, and pathway signatures. The use of prior knowledge in CARNIVAL enables capturing a broad set of upstream cellular processes and regulators, leading to a higher accuracy when benchmarked against related tools. Implementation as an integer linear programming (ILP) problem guarantees efficient computation. As a case study, we applied CARNIVAL to contextualize signaling networks from gene expression data in IgA nephropathy, a condition that can lead to chronic kidney disease. CARNIVAL identified specific signaling pathways and associated mediators dysregulated in IgAN including WNT and TGF-β, that we subsequently validated experimentally. These results demonstrated how CARNIVAL generates hypotheses on potential upstream alterations that propagate through signaling networks, providing insights into diseases.

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“…In summary, EGFR activation has dual effects in AKI or CKD, ameliorating renal damage in experimental AKI by activating the regenerative process that occurs following acute renal damage through the induction of proliferation and migration of tubular cells. In contrast, EGFR activation exerted deleterious effects on CKD by activation of a fibrotic-related process, as observed in long-term models of renal damage [42, 70, 119, 120] (Figure 3).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, upregulation of the EGFR pathway (including several of its ligands, as TGFA, HBEGF, and CTGF) has been described in human and experimental chronic renal pathologies, including glomerulonephritis, diabetic nephropathy, transplant rejection, and polycystic kidney disease [63–65], as well as in experimental models of acute kidney injury (AKI), such as ischemia/reperfusion or folic acid administration [66–68]. Intensive research in many experimental studies has shown that EGFR blockade exerts beneficial effects in progressive kidney disease, mainly ameliorating fibrosis [69, 70]. However, EGFR inhibition in AKI models exerts opposite results, presenting deleterious effects.…”

Section: Introductionmentioning

confidence: 99%

“…However, the role of CTGF in AKI has not been investigated in depth. A recent study by our group described the beneficial effects of CTGF gene deletion, reducing proliferation, the induction of the G2M phase of cellular cycle, and fibrosis in the kidney using a model of CTGF injection over 10 days [70]. Near total inhibition of CTGF below baseline levels reduced tubulointerstitial fibrosis in different models of renal damage, such as folic acid administration or obstructive nephropathy [70, 208].…”

Section: Introductionmentioning

confidence: 99%

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Role of Epidermal Growth Factor Receptor (EGFR) and Its Ligands in Kidney Inflammation and Damage

Rayego‐Mateos

Rodrigues-Díez

Morgado‐Pascual

et al. 2018

Mediators of Inflammation

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122

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Chronic kidney disease (CKD) is characterized by persistent inflammation and progressive fibrosis, ultimately leading to end-stage renal disease. Although many studies have investigated the factors involved in the progressive deterioration of renal function, current therapeutic strategies only delay disease progression, leaving an unmet need for effective therapeutic interventions that target the cause behind the inflammatory process and could slow down or reverse the development and progression of CKD. Epidermal growth factor receptor (EGFR) (ERBB1), a membrane tyrosine kinase receptor expressed in the kidney, is activated after renal damage, and preclinical studies have evidenced its potential as a therapeutic target in CKD therapy. To date, seven official EGFR ligands have been described, including epidermal growth factor (EGF) (canonical ligand), transforming growth factor-α, heparin-binding epidermal growth factor, amphiregulin, betacellulin, epiregulin, and epigen. Recently, the connective tissue growth factor (CTGF/CCN2) has been described as a novel EGFR ligand. The direct activation of EGFR by its ligands can exert different cellular responses, depending on the specific ligand, tissue, and pathological condition. Among all EGFR ligands, CTGF/CCN2 is of special relevance in CKD. This growth factor, by binding to EGFR and downstream signaling pathway activation, regulates renal inflammation, cell growth, and fibrosis. EGFR can also be “transactivated” by extracellular stimuli, including several key factors involved in renal disease, such as angiotensin II, transforming growth factor beta (TGFB), and other cytokines, including members of the tumor necrosis factor superfamily, showing another important mechanism involved in renal pathology. The aim of this review is to summarize the contribution of EGFR pathway activation in experimental kidney damage, with special attention to the regulation of the inflammatory response and the role of some EGFR ligands in this process. Better insights in EGFR signaling in renal disease could improve our current knowledge of renal pathology contributing to therapeutic strategies for CKD development and progression.

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

Cited by 59 publications

References 84 publications

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

Role of Epidermal Growth Factor Receptor (EGFR) and Its Ligands in Kidney Inflammation and Damage

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