Gremlin Is a Downstream Profibrotic Mediator of Transforming Growth Factor-Beta in Cultured Renal Cells

被引：45

作者：

Rodrigues-Diez, Raquel ^{[1
]}

Lavoz, Carolina ^{[1
]}

Carvajal, Gisselle ^{[1
]}

Rayego-Mateos, Sandra ^{[1
]}

Rodrigues Diez, Raul R. ^{[1
]}

Ortiz, Alberto ^{[2
]}

Egido, Jesus ^{[3
]}

Mezzano, Sergio ^{[4
]}

Ruiz-Ortega, Marta ^{[1
]}

机构：

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

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

[3] Univ Autonoma Madrid, Renal Res Lab, Fdn Jimenez Diaz, Madrid, Spain

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

来源：

NEPHRON EXPERIMENTAL NEPHROLOGY | 2012年 / 122卷 / 1-2期

关键词：

Gremlin; Transforming growth factor-beta; Renal fibrosis; Epithelial mesenchymal transition; BONE MORPHOGENETIC PROTEIN; TO-MESENCHYMAL TRANSITION; ANTAGONIST; EXPRESSION; IDENTIFICATION; DECREASE; KIDNEY; GENE;

D O I：

10.1159/000346575

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：

100201 [内科学]; 100221 [泌尿外科学];

摘要：

Background/Aims: Chronic kidney disease is characterized by accumulation of extracellular matrix in the tubulointerstitial area. Fibroblasts are the main matrix-producing cells. One source of activated fibroblasts is the epithelial mesenchymal transition (EMT). In cultured tubular epithelial cells, transforming growth factor-beta (TGF-beta(1)) induced Gremlin production associated with EMT phenotypic changes, and therefore Gremlin has been proposed as a downstream TGF-beta(1) mediator. Gremlin is a developmental gene upregulated in chronic kidney diseases associated with matrix accumulation, but its direct role in the modulation of renal fibrosis and its relation with TGF-beta has not been investigated. Methods: Murine renal fibroblasts and human tubular epithelial cells were studied. Renal fibrosis was determined by evaluation of key profibrotic factors, extracellular matrix proteins (ECM) and EMT markers by Western blot/confocal microscopy or real-time PCR. Endogenous Gremlin was targeted with small interfering RNA. Results: In murine fibroblasts, stimulation with recombinant Gremlin upregulated profibrotic genes, such as TGF-beta(1), and augmented the production of ECM proteins, including type I collagen. The blockade of endogenous Gremlin with small interfering RNA inhibited TGF-beta(1)-induced ECM upregulation. In tubular epithelial cells Gremlin also increased profibrotic genes and caused EMT changes: phenotypic modulation to myofibroblast-like morphology, loss of epithelial markers and induction of mesenchymal markers. Moreover, Gremlin gene silencing inhibited TGF-beta(1)-induced EMT changes. Conclusions: Gremlin directly activates profibrotic events in cultured renal fibroblasts and tubular epithelial cells. Moreover, endogenous Gremlin blockade inhibited TGF-beta-mediated matrix production and EMT, suggesting that Gremlin could be a novel therapeutic target for renal fibrosis. Copyright (C) 2013 S. Karger AG, Basel

引用

页码：62 / 74

页数：13

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