EGF Receptor as a Drug Target in Arterial Hypertension

Bełtowski, Jerzy; Łowicka, Ewelina

doi:10.2174/138955709788167619

Cited by 16 publications

(15 citation statements)

References 95 publications

(119 reference statements)

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“…EGFR is a plasma membrane tyrosine kinase which may be activated by its cognate ligand, epidermal growth factor (EGF), and several other proteins like heparin-binding epidermal growth factor (HB-EGF) [37, 38]. EGFR is highly expressed in renal tubules and its peptide ligands are abundant in urine.…”

Section: Pparγ-c-src-egfr-erk Pathwaymentioning

confidence: 99%

“…However, apart from its ligands, EGFR may be activated by many other factors such as angiotensin II, endothelin-1, catecholamines, and aldosterone; the phenomenon is referred to as “transactivation.” Several mechanisms of EGFR transactivation have been described among which two are the most important: (i) stimulation of metalloprotease-dependent cleavage of HB-EGF from its inactive membrane-bound precursor and (ii) direct phosphorylation of intracellular EGFR domain by c-Src. Transactivation of EGFR by these factors has been observed in blood vessels and the kidney and may contribute to the development of arterial hypertension by increasing vascular tone and/or tubular Na + reabsorption [38]. Indeed, EGFR inhibitors such as AG1478 reduce vascular tone and blood pressure in several experimental models of hypertension [38, 39].…”

Section: Pparγ-c-src-egfr-erk Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Thiazolidinedione-Induced Fluid Retention: Recent Insights into the Molecular Mechanisms

2013

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Peroxisome proliferator-activated receptor-γ (PPARγ) agonists such as rosiglitazone and pioglitazone are used to improve insulin sensitivity in patients with diabetes mellitus. However, thiazolidinediones induce fluid retention, edema, and sometimes precipitate or exacerbate heart failure in a subset of patients. The mechanism through which thiazolidinediones induce fluid retention is controversial. Most studies suggest that this effect results from the increase in tubular sodium and water reabsorption in the kidney, but the role of specific nephron segments and sodium carriers involved is less clear. Some studies suggested that PPARγ agonist stimulates Na+ reabsorption in the collecting duct by activating epithelial Na+ channel (ENaC), either directly or through serum and glucocorticoid-regulated kinase-1 (SGK-1). However, other studies did not confirm this mechanism and even report the suppression of ENaC. Alternative mechanisms in the collecting duct include stimulation of non-ENaC sodium channel or inhibition of chloride secretion to the tubular lumen. In addition, thiazolidinediones may augment sodium reabsorption in the proximal tubule by stimulating the expression and activity of apical Na+/H+ exchanger-3 and basolateral Na+-HCO3 − cotransporter as well as of Na+,K+-ATPase. These effects are mediated by PPARγ-induced nongenomic transactivation of the epidermal growth factor receptor and downstream extracellular signal-regulated kinases (ERK).

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Section: Pparγ-c-src-egfr-erk Pathwaymentioning

confidence: 99%

Section: Pparγ-c-src-egfr-erk Pathwaymentioning

confidence: 99%

Thiazolidinedione-Induced Fluid Retention: Recent Insights into the Molecular Mechanisms

2013

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“…This observation is noteworthy as the epidermal growth factor receptor (EGFR) may contribute to the development of hypertension by regulating vascular tone and renal sodium handling [51]. Synthetic EGFR inhibitors also reduce blood pressure in some experimental models of hypertension and have been suggested as a novel target for antihypertensive therapy [52].…”

Section: Discussionmentioning

confidence: 99%

Genetic markers of bevacizumab-induced hypertension

et al. 2014

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Purpose There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bevacizumab-induced hypertension. Experimental design Germline DNA was available from 1,631 patients receiving bevacizumab-containing therapy for advanced solid tumors. Overall, 194 white patients had grade 1-4 bevacizumab-induced hypertension. In total, 236 single nucleotide polymorphisms (SNPs) located in VEGF-A, VEGF-A receptors (FLT1 and KDR), and other genes were selected using a SNP tagging approach and genotyped. A logistic regression on individual patient data was performed after adjustment for cancer type and five other covariates. Results Ten SNPs were associated with bevacizumabinduced hypertension (P B 0.05), but none surpassed the threshold adjusted for multiple testing (P \ 0.0002). The most significant VEGF-A pathway SNP was rs1680695 in EGLN3 [allelic odds ratio (OR) 1.50 [95 % confidence interval (Cl) 1.09-2.07], P = 0.012]. Two additional SNPs, rs4444903 in EGF and rs2305949 in KDR, were associated with hypertension (allelic OR 1.57 [95 % CI 1.17-2.11], P = 0.0025; allelic OR 0.62 [95 % CI 0.42-0.93], P = 0.020, respectively) and closely linked to nearby functional variants. Consistent with previous reports, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (OR 1.41 [95 % CI 1.04-1.92], P = 0.028). Conclusions The genes described in this large genetic analysis using pooled datasets warrant further functional 123 Angiogenesis (2014) 17:685-694 DOI 10.1007 investigation regarding their role in mediating bevacizumab-induced hypertension.

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“…It has been more recently reported that EGFR activation may contribute to the development of hypertension by regulating vascular tone and renal sodium handling [21]. Hence EGFR inhibitors have been used to reduce blood pressure in experimental models of hypertension, suggesting that EGFR is a novel target for salt sensitive hypertension [24]. We have previously demonstrated that EGF and high-glucose-induced NHE3 expression and activity in the proximal tubule is EGFR dependent with downstream activation of Sgk1 [1].…”

Section: Discussionmentioning

confidence: 99%

“…EGFRs have been recognised as key targets in anticancer therapy and EGFR inhibitors are increasingly used in the treatment of cancer with no reported renal toxicity, despite such patients being at increased risk of acute renal injury, predominantly due to sepsis. The major side effect of targeting the EGFR clinically is inflammatory reactions in the skin [24]. Hence targeting the EGFR in combination with the PPAR γ agonist has the potential to be beneficial in regulating nephromegaly, matrix expansion, and fibrosis in addition to excessive sodium reabsorption observed in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Combined Effects of PPARγAgonists and Epidermal Growth Factor Receptor Inhibitors in Human Proximal Tubule Cells

et al. 2013

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We aimed to determine whether epidermal growth factor receptor (EGFR) inhibition, in addition to a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, prevents high-glucose-induced proximal tubular fibrosis, inflammation, and sodium and water retention in human proximal tubule cells exposed to normal glucose; high glucose; high glucose with the PPARγ agonist pioglitazone or with the P-EGFR inhibitor, gefitinib; or high glucose with both pioglitazone and gefitinib. We have shown that high glucose increases AP-1 and NFκB binding activity, downstream phosphorylation of EGFR and Erk1/2, and fibronectin and collagen IV expression. Pioglitazone reversed these effects but upregulated NHE3 and AQP1 expression. Gefitinib inhibited high glucose induced fibronectin and collagen IV, and EGFR and Erk1/2 phosphorylation and reversed pioglitazone-induced increases in NHE3 and AQP1 expression. Our data suggests that combination of an EGFR inhibitor and a PPARγ agonist mitigates high-glucose-induced fibrosis and inflammation and reverses the upregulation of transporters and channels involved in sodium and water retention in human proximal tubule cells. Hence EGFR blockade may hold promise, not only in limiting tubulointerstitial pathology in diabetic nephropathy, but also in limiting the sodium and water retention observed in patients with diabetes and exacerbated by PPARγ agonists.

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EGF Receptor as a Drug Target in Arterial Hypertension

Cited by 16 publications

References 95 publications

Thiazolidinedione-Induced Fluid Retention: Recent Insights into the Molecular Mechanisms

Thiazolidinedione-Induced Fluid Retention: Recent Insights into the Molecular Mechanisms

Genetic markers of bevacizumab-induced hypertension

Combined Effects of PPARγAgonists and Epidermal Growth Factor Receptor Inhibitors in Human Proximal Tubule Cells

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