Epidermal Growth Factor Receptor Signaling in the Kidney

Melenhorst, Wynand B. W. H.; Mulder, Gemma M.; Xi, Qi; Hoenderop, Joost G. J.; Kimura, Keita; Eguchi, Satoru; Goor, Harry van

doi:10.1161/hypertensionaha.108.113860

Cited by 95 publications

(118 citation statements)

References 69 publications

(73 reference statements)

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“…Signaling by EGF receptors is essential for growth, migration, and proliferation of cells (6). The EGF receptor family (ErbB receptors) consists of four receptors: the EGF/ErbB1, HER-2, ErbB3, and ErbB4 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…In this respect, intervention in the EGF receptor pathway may be of interest because this pathway is involved with growth, migration, and proliferation of renal tubular cells (6). Dysregulation of this pathway has been suggested to play a role in the pathogenesis of ADPKD (7).…”

Section: Introductionmentioning

confidence: 99%

“…The urinary excretion of the EGF(ErbB1) receptor ligands is expected to be representative for the activity of the EGF receptor pathway because binding of the ligands to the EGF receptor will activate this pathway (6). Excretion of EGF receptor ligands in human ADPKD has not been investigated yet.…”

Section: Introductionmentioning

confidence: 99%

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Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Harskamp¹,

Gansevoort²,

Boertien³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor ligands were measured in patients with ADPKD at baseline and after treatment with a vasopressin V2 receptor antagonist (V2RA) because this information might provide a rationale for future V2RA combination therapy.Design, setting, participants, & measurements Blood and urine concentrations of the EGF receptor ligands heparin-binding (HB)-EGF, EGF, and TGF-a were measured by ELISAs in 27 patients with ADPKD who participated in a single-center study investigating a V2RA in 2011-2013 and in 27 controls who were selected from a general population-based observational study. Cyst fluid concentrations were also measured. In patients with ADPKD, ligands were measured at baseline, after 3-week treatment with a V2RA, and 3 weeks after drug withdrawal. The measured GFR (mGFR) was determined by iothalamate infusion, and total kidney volume was measured by magnetic resonance imaging.Results Urinary HB-EGF excretion and plasma concentration were higher in patients with ADPKD than in controls (median, . In contrast, urinary EGF excretion and plasma EGF concentration were lower in patients with ADPKD, whereas TGF-a did not differ between patients and controls. Higher HB-EGF excretion was correlated with more severe disease, assessed as lower mGFR (r=20.39; P=0.05), higher total kidney volume (r=0.39; P=0.05), and higher urinary excretion of albumin and heart-type fatty acid-binding protein, whereas higher EGF excretion and TGF-a excretion were negatively correlated with disease severity. During V2RA treatment, HB-EGF excretion increased (from 1.4 [1.2-1.9] to 2.4 [2.1-3.1] mg/24 hours; P,0.001).1 ConclusionIn patients with ADPKD, higher urinary HB-EGF excretion is correlated with more severe disease. Whether this association is causal needs to be investigated in intervention studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Harskamp¹,

Gansevoort²,

Boertien³

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…Recombinant VEGF-A 165 was purchased from RELIATech GmbH (Brauschweig, Germany); DLL4 (rDLL4) extracellular domain was from R&D Systems (Abingdon, Oxfordshire, UK); L685,458 (␥-secretase inhibitor) from Calbiochem (Nottingham, UK); and IMC1121b (human VEGFR-2 inhibitor) and IMC-18F1 (human VEGFR-1 inhibitor) (18,19) were both kindly provided by ImClone Systems Corp. (New York, NY). ADAM inhibitors GI250423X (ADAM-10 inhibitors) and GW28026X (ADAM-10/17 inhibitor) (20) were both kindly provided by GlaxoSmithKline.…”

Section: Methodsmentioning

confidence: 99%

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Caolo

Akker

Verbruggen

et al. 2010

Journal of Biological Chemistry

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The DELTA like-4 ligand (DLL4) belongs to the highly conserved NOTCH family and is specifically expressed in the endothelium. DLL4 regulates crucial processes in vascular growth, including endothelial cell (EC) sprouting and arterial specification. Its expression is increased by VEGF-A. In the present study, we show that VEGF-induced DLL4 expression depends on NOTCH activation. VEGF-induced DLL4 expression was prevented by the blockage of NOTCH signaling with ␥-secretase or ADAM inhibitors in human cardiac microvascular ECs. Similar to VEGF-A, recombinant DLL4 itself stimulated NOTCH signaling and resulted in up-regulation of DLL4, suggesting a positive feed-forward mechanism. These effects were abrogated by NOTCH inhibitors but not by inhibition of VEGF signaling. NOTCH activation alone suffices to induce DLL4 expression as illustrated by the positive effect of NOTCH intracellular domain (NICD)-1 or -4 overexpression. To discriminate between NICD/RBP-J and FOXC2-regulated DLL4 expression, DLL4 promoter activity was assessed in promoter deletion experiments. NICD induced promoter activity was dependent on RBP-J site but independent of the FOXC2 binding site. Accordingly, constitutively active FOXC2 did not affect DLL4 expression. The notion that the positive feed-forward mechanism might propagate NOTCH activation to neighboring ECs was supported by our observation that DLL4-eGFP-transfected ECs induced DLL4 expression in nontransfected cells in their vicinity. In summary, our data provide evidence for a mechanism by which VEGF or ligand-induced NOTCH signaling up-regulates DLL4 through a positive feedforward mechanism. By this mechanism, DLL4 could propagate its own expression and enable synchronization of NOTCH expression and signaling between ECs.The NOTCH family encompasses a fundamental signaling pathway involving four receptors (NOTCH-1, -2, -3, and -4) and, in vertebrates, five cognate ligands (DLL-1, -3, and -4, and JAGGED-1 and -2). Cell-cell contact is a prerequisite for NOTCH signaling as all members are membrane bound. The first activation step upon receptor-ligand interaction involves cleavage of the extracellular domain of the NOTCH receptor by ADAM (a disintegrin and metalloprotease). Subsequently, the ␥-secretase complex instigates a second proteolytic cleavage resulting in the release of the NOTCH intracellular domain (NICD) 2 into the cytoplasm. Next, the NICD translocates to the nucleus, where it associates with the Recombinant signal binding protein for immunoglobulin kappa J region (RBP-J) CBF1/RBP-J, Su(H), Lag1 (CSL) transcription factor to initiate the transcription of its downstream targets basic helix-loop-helix proteins HES (hairy/enhancer of split) and hairy related transcription factors (HRT, HEY, and

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“…EGF receptor signalling in the kidney has been recognized as a major regulator of electrolyte (including magnesium) homeostasis [102]. It is proposed that this function is performed by the receptor independent actions of EGF (Figure 1).…”

Section: Physiological Role Of Pathway 1 To Inhibit Renal Sodium Reabmentioning

confidence: 99%

A Single Initiating Cause of Hypertension; Potential for Primary Prevention

Sambhi¹

2014

J Hypertens

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Epidermal Growth Factor Receptor Signaling in the Kidney

Cited by 95 publications

References 69 publications

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

A Single Initiating Cause of Hypertension; Potential for Primary Prevention

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