Gremlin is a downstream profibrotic mediator of transforming growth factor-beta in cultured renal cells.

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-β1) induced Gremlin production associated with EMT phenotypic changes, and therefore Gremlin has been proposed as a downstream TGF-β1 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. 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. In murine fibroblasts, stimulation with recombinant Gremlin upregulated profibrotic genes, such as TGF-β1, and augmented the production of ECM proteins, including type I collagen. The blockade of endogenous Gremlin with small interfering RNA inhibited TGF-β1-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-β1-induced EMT changes. 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.

Rodrigues-Diez R ，Lavoz C ，Carvajal G ，Rayego-Mateos S ，Rodrigues Diez RR ，Ortiz A ，Egido J ，Mezzano S ，Ruiz-Ortega M ... -  《nephron experimental nephrology》

Gremlin activates the Smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells.

Rodrigues-Diez R ，Rodrigues-Diez RR ，Lavoz C ，Carvajal G ，Droguett A ，Garcia-Redondo AB ，Rodriguez I ，Ortiz A ，Egido J ，Mezzano S ，Ruiz-Ortega M ... -  《-》

TGF-β2 induces transdifferentiation and fibrosis in human lens epithelial cells via regulating gremlin and CTGF.

Transforming growth factor (TGF)-β2, gremlin and connective tissue growth factor (CTGF) are known to play important roles in the induction of epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) synthesis. However, the complex functional relationship among gremlin, CTGF and TGF-β2 in the induction of EMT and ECM synthesis in human lens epithelial cells (HLECs) has not been reported. In this study, we found that TGF-β2, CTGF and gremlin can individually induce the expression of α-smooth muscle actin (α-SMA), fibronectin (Fn), collagen type I (COL-I), Smad2 and Smad3 in HLECs. Blockade of CTGF and gremlin effectively inhibited TGF-β2-induced expression of α-SMA, Fn, COL-I, Smad2, and Smad3 in HLECs. Furthermore blockade of Smad2 and Smad3 effectively inhibited CTGF and gremlin induced expression of α-SMA, Fn, COL-I in HLECs. In conclusion, TGF-β2, CTGF and gremlin are all involved in EMT and ECM synthesis via activation of Smad signaling pathway in HLECs. Specifically silencing CTGF and gremlin can effectively block the TGF-β2-induced EMT, ECM synthesis due to failure in activation of Smad signaling pathway in HLECs.

Ma B ，Kang Q ，Qin L ，Cui L ，Pei C ... -  《-》

Gremlin: a novel mediator of epithelial mesenchymal transition and fibrosis in chronic allograft nephropathy.

Carvajal G ，Droguett A ，Burgos ME ，Aros C ，Ardiles L ，Flores C ，Carpio D ，Ruiz-Ortega M ，Egido J ，Mezzano S ... -  《TRANSPLANTATION PROCEEDINGS》

Expression of gremlin, a bone morphogenetic protein antagonist, in glomerular crescents of pauci-immune glomerulonephritis.

Mezzano S ，Droguett A ，Burgos ME ，Aros C ，Ardiles L ，Flores C ，Carpio D ，Carvajal G ，Ruiz-Ortega M ，Egido J ... -  《NEPHROLOGY DIALYSIS TRANSPLANTATION》