In:
Nephron Experimental Nephrology, S. Karger AG, Vol. 122, No. 1-2 ( 2013-3-14), p. 62-74
Kurzfassung:
〈 b 〉 〈 i 〉 Background/Aims: 〈 /i 〉 〈 /b 〉 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-β (TGF-β 〈 sub 〉 1 〈 /sub 〉 ) induced Gremlin production associated with EMT phenotypic changes, and therefore Gremlin has been proposed as a downstream TGF-β 〈 sub 〉 1 〈 /sub 〉 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-β has not been investigated 〈 i 〉 . 〈 /i 〉 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 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. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 In murine fibroblasts, stimulation with recombinant Gremlin upregulated profibrotic genes, such as TGF-β 〈 sub 〉 1 〈 /sub 〉 , and augmented the production of ECM proteins, including type I collagen. The blockade of endogenous Gremlin with small interfering RNA inhibited TGF-β 〈 sub 〉 1 〈 /sub 〉 -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 in-duction of mesenchymal markers. Moreover, Gremlin gene silencing inhibited TGF-β 〈 sub 〉 1 〈 /sub 〉 -induced EMT changes. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 Gremlin directly activates profibrotic events in cul-tured renal fibroblasts and tubular epithelial cells. Moreover, endogenous Gremlin blockade inhibited TGF-β-mediated matrix production and EMT, suggesting that Gremlin could be a novel therapeutic target for renal fibrosis.
Materialart:
Online-Ressource
ISSN:
1660-2129
Sprache:
Englisch
Verlag:
S. Karger AG
Publikationsdatum:
2013
ZDB Id:
2098337-2
