Role of EGF Receptor Activation in Angiotensin II–Induced Renal Epithelial Cell Hypertrophy

Chen, Shiguo; Chen, Jian Kang; Neilson, Eric G.; Harris, Raymond C.

doi:10.1681/asn.2005111163

Cited by 61 publications

(57 citation statements)

References 46 publications

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“…However, proximal tubular TGFb and p smad2/3 expression after Ang II infusion were markedly inhibited in either erlotinibtreated or EGFR ptKO kidneys ( Figure 3). To determine the link between the EGFR-mediated fibrosis and TGFb expression, we first utilized AT1R/Cl4 cells, an Ang II-responsive proximal tubule cell line, 17 to examine the mechanism by which Ang II activates TGFb in proximal tubular cells. Ang II increased p Smad2/3 expression within 10 minutes, with persistent expression at 3 hours ( Figure 3E).…”

Section: Egfr Inhibition Attenuates Tgfb and Smad2/3 Expressionmentioning

confidence: 99%

“…Knocking down EGFR expression with small interfering RNA (siRNA) inhibited both early and persistent ERK 1/2 phosphorylation in response to Ang II ( Figure 4B). Although Ang II transactivates EGFR in AT1R/Cl4 cells by metalloproteinase-mediated cleavage and release of soluble HB-EGF within 5 minutes, 17 preincubation with the HB-EGF inhibitor, CRM197, only partially inhibited the early phase of ERK 1/2 phosphorylation ( Figure 4C) and did not affect the later phases of ERK 1/2 phosphorylation at all, indicating the late phase of Ang II-mediated ERK 1/2 activation to be independent of EGFR transactivation by release of soluble HB-EGF.…”

Section: Egfr Inhibition Attenuates Tgfb and Smad2/3 Expressionmentioning

confidence: 99%

“…17 Cells were made quiescent in serum free culture medium for 24 hours followed by treatment with different reagents for indicated times. For induction of dedifferentiation in culture, cells were cultured in DMEM-F-12 containing 0.5% serum and 100 nM Ang II and fresh medium was changed daily for up to 7 days.…”

Section: Cell Culturementioning

confidence: 99%

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EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis

Chen¹,

Chen²,

Nagai³

et al. 2012

Journal of the American Society of Nephrology

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239

247

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The mechanisms by which angiotensin II (Ang II) promotes renal fibrosis remain incompletely understood. Ang II both stimulates TGFb signaling and activates the EGF receptor (EGFR), but the relative contribution of these pathways to renal fibrogenesis is unknown. Using a murine model with EGFRdeficient proximal tubules, we demonstrate that upstream activation of EGFR-dependent ERK signaling is critical for mediating sustained TGFb expression in renal fibrosis. Persistent activation of the Ang II receptor stimulated ROS-dependent phosphorylation of Src, leading to sustained EGFRdependent signaling for TGFb expression. Either genetic or pharmacologic inhibition of EGFR significantly decreased TGFb-mediated fibrogenesis. We conclude that TGFb-mediated tissue fibrosis relies on a persistent feed-forward mechanism of EGFR/ERK activation through an unexpected signaling pathway, highlighting EGFR as a potential therapeutic target for modulating tissue fibrogenesis.

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Section: Egfr Inhibition Attenuates Tgfb and Smad2/3 Expressionmentioning

confidence: 99%

Section: Egfr Inhibition Attenuates Tgfb and Smad2/3 Expressionmentioning

confidence: 99%

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EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis

Chen¹,

Chen²,

Nagai³

et al. 2012

Journal of the American Society of Nephrology

Self Cite

239

247

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“…Interestingly, it has been previously shown that Ang-II-mediated injury associates with activation of these kinases. 128 Modified from reference 125.…”

Section: Transactivation Of the Egf Receptor By Ang IImentioning

confidence: 99%

“…127 These early findings provide evidence of a potential interaction between Ang II and EGF-mediated signaling, and Chen and colleagues recently found evidence for a role of heparin-binding EGF (HB-EGF) in Ang II-induced tubular hypertrophy. 128 Axel Ulrich's group discovered a pathway in 1996 for how G-protein coupled receptors such as the AT1R could phosphorylate and activate the EGFR. 129 Ang II was initially not studied, but the investigators found that ET-1, lysophosphatic acid, and thrombin all activate G-coupled receptors lacking the kinase domain by phosphorylating tyrosine residues on the EGFR and thereby activating other downstream kinases.…”

Section: Transactivation Of the Egf Receptor By Ang IImentioning

confidence: 99%

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

Rüster

Wolf

2011

Journal of the American Society of Nephrology

171

150

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Chronic kidney disease (CKD) is increasing worldwide. Although the cause of its progression is multifactorial, 1-3 activation of the renin-angiotensin-aldosterone system (RAAS) is a key effector and RAAS inhibitors are among the beststudied renoprotective agents. 4 -7 Although the RAAS is complex, with new peptides such as angiotensin 1-7 and angiotensin IV exhibiting profibrotic effects by binding to specific receptors as well as observations that aldosterone and even renin itself can stimulate fibrogenesis in the kidney, 8 -12 and angiotensin II (Ang II) blockade can stimulate renin release, 13 the review presented here focuses exclusively on Ang II as the major component of the RAAS effect on morphogenesis. There are several excellent reviews covering the other components of the RAAS and their profibrotic actions in the kidney. 8 -10,14 The classic view of Ang II as a vasoactive agent involved in local and systemic hemodynamic regulation 15 needs extension to encompass its properties as a morphogenic cytokine with an active role in renal pathology. 16,17 Ang II was first described 2 decades ago as stimulating the hypertrophy of tubular cells and the associated increase in collagen secretion. 18,19 Fibrosis is the final common pathway leading to renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. 20 -22 Ang II modulates renal cell growth and extracellular matrix (ECM) synthesis or degradation. 17,[23][24][25] For example, overexpression of renin and angiotensinogen in rat glomeruli leads to expanded ECM without inducing systemic hypertension. 26,27 The stimulatory effects of Ang II on increased collagen expression depend on various mechanisms. In addition to angiotensin-converting enzyme (ACE), which is the most well known enzyme capable of Ang II formation, other non-ACE Ang II-generating pathways are currently under study. 28 ACE inhibitors also diminish cellular infiltrates and inflammatory markers in many models of renal injury. 29 ANG II AND TGF␤The interactions between Ang II and the TGF␤ axis are multiple and complex (Figure 1). 29 -31 TGF␤ is a fibrogenic and anti-inflammatory cytokine and plays a critical role in the pathophysiology of renal injury. 32,33 Ang II stimulates transcription and synthesis of TGF␤, particularly TGF␤1, in cultured murine proximal tubular cells and also upregulates specific receptors for TGF␤, further enhancing its profibrogenic action. 34 -36 Ang II directly stimulates complex interactions in the ABSTRACTInhibitors of the renin-angiotensin-aldosterone system attenuate glomerulosclerosis and interstitial fibrosis. Although the mechanisms underlying their antifibrotic effects are complex, angiotensin II (Ang II) emerges as a major profibrogenic cytokine. Ang II modulates renal cell growth, extracellular matrix synthesis, and degradation by multiple fibrotic pathways. One of the main targets of Ang II in renal fibrosis is TGF␤. Many, but not all, of the stimulatory effects of Ang II on fibrogenesis depend on the induction...

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Classical Renin‐Angiotensin System in Kidney Physiology

Sparks

Crowley

Gurley

et al. 2014

Comprehensive Physiology

461

429

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The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the “classical” renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the “classical” renin-angiotensin system, with an emphasis on new developments and modern concepts.

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Role of EGF Receptor Activation in Angiotensin II–Induced Renal Epithelial Cell Hypertrophy

Cited by 61 publications

References 46 publications

EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis

EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis

Angiotensin II as a Morphogenic Cytokine Stimulating Renal Fibrogenesis

Classical Renin‐Angiotensin System in Kidney Physiology

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