Juxtacrine activation of EGFR regulates claudin expression and increases transepithelial resistance

Singh, Amar B.; Sugimoto, Keisuke; Dhawan, Punita; Harris, Raymond C.

doi:10.1152/ajpcell.00274.2007

Cited by 42 publications

(34 citation statements)

References 51 publications

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“…In Madin-Darby canine kidney epithelial cells, HB-EGF treatment increased transepithelial resistance and decreased permeability (Singh et al, 2007). Likewise, in primary canine gastric epithelial cells, EGF increased transepithelial resistance and decreased paracellular permeability of the cells (Chen et al, 2001).…”

Section: Discussionmentioning

confidence: 91%

Bradykinin Decreases Podocyte Permeability through ADAM17-Dependent Epidermal Growth Factor Receptor Activation and Zonula Occludens-1 Rearrangement

Dey

Baldys²,

Sumter³

et al. 2010

J Pharmacol Exp Ther

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Recent data show that increases in bradykinin (BK) concentration contribute to the beneficial effects of angiotensin-converting enzyme inhibitor (ACEI) treatment in chronic kidney disease. However, the possible role of BK in attenuated proteinuria, often seen in ACEI-treated patients, is not well studied. Here, we report that BK decreases mouse podocyte permeability through rearrangement of the tight junction protein zonula occludens-1 (ZO-1) and identify some of the major signaling events leading to permeability change. We show that BK2 receptor (BK2R) stimulation transactivates the epidermal growth factor receptor (EGFR). EGFR transactivation is mediated by a disintegrin and metalloenzyme (ADAM) family members, which are required for both extracellular signalregulated kinase (ERK) and EGFR activation by BK. Using a genesilencing approach we observed that both BK-induced ERK activation and BK-induced permeability decrease in podocytes is attenuated by ADAM17 down-regulation, and we identified epiregulin (ER) as the EGFR ligand participating in ADAM-dependent BK2R-EGFR cross-talk. EGFR inhibition attenuated both ZO-1 rearrangement and BK-induced permeability decreases in podocyte. We propose that ZO-1 redistribution is an important element of BK-induced permeability change and the signaling events involved in ZO-1 rearrangement include transactivation of the EGFR via ADAM17 activation and ER shedding. Our data indicate that ADAM17 and the EGFR may be potential novel therapeutic targets in diabetic nephropathy and other chronic kidney diseases.

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Section: Discussionmentioning

confidence: 91%

Bradykinin Decreases Podocyte Permeability through ADAM17-Dependent Epidermal Growth Factor Receptor Activation and Zonula Occludens-1 Rearrangement

Dey

Baldys²,

Sumter³

et al. 2010

J Pharmacol Exp Ther

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“…EGF has been shown to prevent stress-induced hyperpermeability in a variety of cell types by altering expression and subcellular localization of claudin-2, claudin-3, and occludin (3,4,14,46,48,49). Additionally, intestinal paracellular permeability is regulated, in part, by the ratio of claudin isoforms within the tight junction complex (25), and the pore-forming protein claudin-2 has been associated with increased paracellular permeability (19).…”

Section: Discussionmentioning

confidence: 99%

Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis

Clark¹,

Gan²,

Samocha³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Clark JA, Gan H, Samocha AJ, Fox AC, Buchman TG, Coopersmith CM. Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis. Am J Physiol Gastrointest Liver Physiol 297: G471-G479, 2009. First published July 1, 2009 doi:10.1152/ajpgi.00012.2009.-Systemic administration of epidermal growth factor (EGF) decreases mortality in a murine model of septic peritonitis. Although EGF can have direct healing effects on the intestinal mucosa, it is unknown whether the benefits of systemic EGF in peritonitis are mediated through the intestine. Here, we demonstrate that enterocyte-specific overexpression of EGF is sufficient to prevent intestinal barrier dysfunction and improve survival in peritonitis. Transgenic FVB/N mice that overexpress EGF exclusively in enterocytes (IFABP-EGF) and wild-type (WT) mice were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability, expression of the tight junction proteins claudins-1, -2, -3, -4, -5, -7, and -8, occludin, and zonula occludens-1; villus length; intestinal epithelial proliferation; and epithelial apoptosis were evaluated. A separate cohort of mice was followed for survival. Peritonitis induced a threefold increase in intestinal permeability in WT mice. This was associated with increased claudin-2 expression and a change in subcellular localization. Permeability decreased to basal levels in IFABP-EGF septic mice, and claudin-2 expression and localization were similar to those of sham animals. Claudin-4 expression was decreased following CLP but was not different between WT septic mice and IFABP-EGF septic mice. Peritonitis-induced decreases in villus length and proliferation and increases in apoptosis seen in WT septic mice did not occur in IFABP-EGF septic mice. IFABP-EGF mice had improved 7-day mortality compared with WT septic mice (6% vs. 64%). Since enterocyte-specific overexpression of EGF is sufficient to prevent peritonitis-induced intestinal barrier dysfunction and confers a survival advantage, the protective effects of systemic EGF in septic peritonitis appear to be mediated in an intestine-specific fashion.

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“…FGF-2 fails to induce angiogenesis in JAM-A-deficient mice (Cooke et al 2006), suggesting a role of JAM-A in FGF-2 signaling, which might be mediated by the PAR3/PAR6/aPKC complex (Ebnet et al 2004). Additionally, EGF signaling seems to affect the expression and localization of several TJ proteins that regulate TJ assembly and barrier functions (Van Itallie et al 1995;Basuroy et al 2006;Wang et al 2006;Flores-Benitez et al 2007;Singh et al 2007), suggesting that EGF signaling could have an indirect role in regulating TJ-nuclear signaling by modulating the activities of the PAR3/ PAR6/aPKC and/or ZO-1/ZONAB pathways.…”

Section: Tight Junction Cross Talk With Growth Factors and Extracellumentioning

confidence: 99%

Junctional Music that the Nucleus Hears: Cell-Cell Contact Signaling and the Modulation of Gene Activity

McCrea

Gu²,

Balda³

2009

Cold Spring Harbor Perspectives in Biology

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Juxtacrine activation of EGFR regulates claudin expression and increases transepithelial resistance

Abstract: Singh AB, Sugimoto K, Dhawan P, Harris RC. Juxtacrine activation of EGFR regulates claudin expression and increases transepithelial resistance.

Cited by 42 publications

References 51 publications

Bradykinin Decreases Podocyte Permeability through ADAM17-Dependent Epidermal Growth Factor Receptor Activation and Zonula Occludens-1 Rearrangement

Bradykinin Decreases Podocyte Permeability through ADAM17-Dependent Epidermal Growth Factor Receptor Activation and Zonula Occludens-1 Rearrangement

Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis

Junctional Music that the Nucleus Hears: Cell-Cell Contact Signaling and the Modulation of Gene Activity

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