EGFR Signaling Promotes TGFβ-Dependent Renal Fibrosis

被引:240
作者
Chen, Jianchun [1 ]
Chen, Jian-Kang [1 ]
Nagai, Kojiro [1 ]
Plieth, David [1 ]
Tan, Mingqi [1 ]
Lee, Tang-Cheng [2 ]
Threadgill, David W. [2 ]
Neilson, Eric G. [1 ,4 ]
Harris, Raymond C. [1 ,3 ,5 ]
机构
[1] Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Dept Cell Biol, Sch Med, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA
[4] N Carolina State Univ, Dept Genet, Raleigh, NC 27695 USA
[5] Dept Vet Affairs, Nashville, TN USA
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2012年 / 23卷 / 02期
基金
美国国家卫生研究院;
关键词
GROWTH-FACTOR RECEPTOR; EPITHELIAL-MESENCHYMAL TRANSITION; ANGIOTENSIN-II; C-SRC; KIDNEY; EXPRESSION; PATHWAY; TRANSACTIVATION; HYPERTROPHY; ACTIVATION;
D O I
10.1681/ASN.2011070645
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
The mechanisms by which angiotensin II (Ang II) promotes renal fibrosis remain incompletely understood. Ang II both stimulates TGF beta signaling and activates the EGF receptor (EGFR), but the relative contribution of these pathways to renal fibrogenesis is unknown. Using a murine model with EGFR-deficient proximal tubules, we demonstrate that upstream activation of EGFR-dependent ERK signaling is critical for mediating sustained TGF beta expression in renal fibrosis. Persistent activation of the Ang II receptor stimulated ROS-dependent phosphorylation of Src, leading to sustained EGFR-dependent signaling for TGF beta expression. Either genetic or pharmacologic inhibition of EGFR significantly decreased TGF beta-mediated fibrogenesis. We conclude that TGF beta-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.
引用
收藏
页码:215 / 224
页数:10
相关论文
共 33 条
[1]   Signal transduction by the TGF-β superfamily [J].
Attisano, L ;
Wrana, JL .
SCIENCE, 2002, 296 (5573) :1646-1647
[2]   c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function [J].
Biscardi, JS ;
Maa, MC ;
Tice, DA ;
Cox, ME ;
Leu, TH ;
Parsons, SJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (12) :8335-8343
[3]   Angiotensin II activates the Smad pathway during epithelial mesenchymal transdifferentiation [J].
Carvajal, Gisselle ;
Rodriguez-Vita, Juan ;
Rodrigues-Diez, Raquel ;
Sanchez-Lopez, Elsa ;
Ruperez, Monica ;
Cartier, Cecile ;
Esteban, Vanesa ;
Ortiz, Alberto ;
Egido, Jesus ;
Mezzano, Sergio A. ;
Ruiz-Ortega, Marta .
KIDNEY INTERNATIONAL, 2008, 74 (05) :585-595
[4]   Mitogenic activity and signaling mechanism of 2-(14,15-epoxyeicosatrienoyl) glycerol, a novel cytochrome P450 arachidonate metabolite [J].
Chen, Jianchun ;
Chen, Jian-Kang ;
Falck, John R. ;
Anjaiah, Siddam ;
Capdevila, Jorge H. ;
Harris, Raymond C. .
MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (08) :3023-3034
[5]   Role of EGF receptor activation in angiotensin II-induced renal epithelial cell hypertrophy [J].
Chen, Jianchun ;
Chen, Jian-Kang ;
Neilson, Eric G. ;
Harris, Raymond C. .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2006, 17 (06) :1615-1623
[6]   Role of mammalian target of rapamycin signaling in compensatory renal hypertrophy [J].
Chen, JK ;
Chen, JC ;
Neilson, EG ;
Harris, RC .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2005, 16 (05) :1384-1391
[7]   Tumor promoter arsenite activates extracellular signal-regulated kinase through a signaling pathway mediated by epidermal growth factor receptor and Shc [J].
Chen, W ;
Martindale, JL ;
Holbrook, NJ ;
Liu, YS .
MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (09) :5178-5188
[8]   Angiotensin II stimulation of VEGF mRNA translation requires production of reactive oxygen species [J].
Feliers, D ;
Gorin, Y ;
Ghosh-Choudhury, G ;
Abboud, HE ;
Kasinath, BS .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2006, 290 (04) :F927-F936
[9]   Prevention of renal vascular and glomerular fibrosis by epidermal growth factor receptor inhibition [J].
François, H ;
Placier, S ;
Flamant, M ;
Tharaux, PL ;
Chansel, D ;
Dussaule, JC ;
Chatziantoniou, C .
FASEB JOURNAL, 2004, 18 (03) :926-+
[10]   NADPH oxidases in the kidney [J].
Gill, Pritmohinder S. ;
Wilcox, Christopher S. .
ANTIOXIDANTS & REDOX SIGNALING, 2006, 8 (9-10) :1597-1607