Angiotensin II activates the Smad pathway during epithelial mesenchymal transdifferentiation

被引：106

作者：

Carvajal, Gisselle ^{[3
]}

Rodriguez-Vita, Juan

Rodrigues-Diez, Raquel

Sanchez-Lopez, Elsa

Ruperez, Monica

Cartier, Cecile

Esteban, Vanesa

Ortiz, Alberto ^{[2
]}

Egido, Jesus ^{[2
]}

Mezzano, Sergio A. ^{[3
]}

Ruiz-Ortega, Marta ^{[1
]}

机构：

[1] Univ Autonoma Madrid, Fdn Jimenez Diaz, Cellular Biol Renal Dis Lab, Madrid 28040, Spain

[2] Univ Autonoma Madrid, Fdn Jimenez Diaz, Renal Unit, Madrid 28040, Spain

[3] Univ Austral Chile, Sch Med, Div Nephrol, Valdivia, Chile

来源：

KIDNEY INTERNATIONAL | 2008年 / 74卷 / 05期

关键词：

angiotensin; Smad; tubuloepithelial cells; fibrosis; TGF-beta;

D O I：

10.1038/ki.2008.213

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：

Epithelial to mesenchymal transdifferentiation is a novel mechanism that promotes renal fibrosis and here we investigated whether known causes of renal fibrosis (angiotensin II and transforming growth factor beta, TGF beta) act through this pathway. We infused angiotensin II into rats for 1 day and found that it activated the Smad pathway which persisted for up to 2 weeks in chronically infused rats. Renal TGF-beta mRNA expression was increased at 3 days and its protein at 2 weeks suggesting Smad pathway activation occurred earlier than TGF-beta upregulation. In cultured human tubuloepithelial cells, angiotensin II caused a rapid activation of Smad signaling independent of TGF-beta however, Smad-dependent transcription after 1 day was TGF-beta mediated. Two weeks of angiotensin II infusion activated genes associated with epithelial mesenchymal transdifferentiation. Stimulation with angiotensin II for 3 days caused transdifferentiation of the cultured epithelial cells by TGF-beta-mediated processes; however, early changes were independent of endogenous TGF-beta. Smad7 overexpression, which blocks Smad2/3 activation, diminished angiotensin II-induced epithelial mesenchymal transdifferentiation. Our results show that angiotensin II activates the Smad signaling system by TGF-beta-independent processes, in vivo and in vitro, causing renal fibrosis.

引用

页码：585 / 595

页数：11

共 31 条

[1] Transdifferentiation of epithelial glomerular cells [J].

Bariéty, J ;

Bruneval, P ;

Hill, GS ;

Mandet, C ;

Jacquot, C ;

Meyrier, A .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (06) :S42-S47

[2] Vimentin and heat shock protein expression are induced in the kidney by angiotensin and by nitric oxide inhibition [J].

Bravo, J ;

Quiroz, Y ;

Pons, H ;

Parra, G ;

Herrera-Acosta, J ;

Johnson, RJ ;

Rodríguez-Iturbe, B .

KIDNEY INTERNATIONAL, 2003, 64 :S46-S51

[3] Influence of connective tissue growth factor antisense oligonucleotide on angiotensin II-induced epithelial mesenchymal transition in HK2 cells [J].

Chen, Long ;

Liu, Bi-cheng ;

Zhang, Xiao-liang ;

Zhang, Jian-dong ;

Liu, Hong ;

Li, Min-xia .

ACTA PHARMACOLOGICA SINICA, 2006, 27 (08) :1029-1036

[4] A SYNTHETIC INHIBITOR OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE [J].

DUDLEY, DT ;

PANG, L ;

DECKER, SJ ;

BRIDGES, AJ ;

SALTIEL, AR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (17) :7686-7689

[5] Transforming growth factor-β regulates tubular epithelial-myofibroblast transdifferentiation in vitro [J].

Fan, JM ;

Ng, YY ;

Hill, PA ;

Nikolic-Paterson, DJ ;

Mu, W ;

Atkins, RC ;

Lan, HY .

KIDNEY INTERNATIONAL, 1999, 56 (04) :1455-1467

[6] Smad7 transgene attenuates peritoneal fibrosis in uremic rats treated with peritoneal dialysis [J].

Guo, Hong ;

Leung, Joseph C. K. ;

Lam, Man Fai ;

Chan, Loretta Y. Y. ;

Tsang, Anita W. L. ;

Lan, Hui Yao ;

Lai, Kar Neng .

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2007, 18 (10) :2689-2703

[7] Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro [J].

Hao, JM ;

Wang, BQ ;

Jones, SC ;

Jassal, DS ;

Dixon, IMC .

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2000, 279 (06) :H3020-H3030

[8] Ultrasound-microbubble-mediated gene transfer of inducible Smad7 blocks transforming growth factor-β signaling and fibrosis in rat remnant kidney [J].

Hou, CC ;

Wang, WS ;

Huang, XR ;

Fu, P ;

Chen, TH ;

Sheikh-Hamad, D ;

Lan, HY .

AMERICAN JOURNAL OF PATHOLOGY, 2005, 166 (03) :761-771

[9] RENAL INJURY FROM ANGIOTENSIN-II - MEDIATED HYPERTENSION [J].

JOHNSON, RJ ;

ALPERS, CE ;

YOSHIMURA, A ;

LOMBARDI, D ;

PRITZL, P ;

FLOEGE, J ;

SCHWARTZ, SM .

HYPERTENSION, 1992, 19 (05) :464-474

[10] ANGIOTENSIN-II STIMULATES EXTRACELLULAR-MATRIX PROTEIN-SYNTHESIS THROUGH INDUCTION OF TRANSFORMING GROWTH-FACTOR-BETA EXPRESSION IN RAT GLOMERULAR MESANGIAL CELLS [J].

KAGAMI, S ;

BORDER, WA ;

MILLER, DE ;

NOBLE, NA .

JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (06) :2431-2437

← 1 2 3 4 →